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New Exome Evidence Points to Old Suspect in Schizophrenia

January 22, 2014. Rare variants in the exome, the protein-coding part of the genome, suggest disruptions to synaptic communication in schizophrenia. Published in two studies in Nature on January 22, these results come from the largest yet exome sequencing efforts, conducted by an international collaboration of researchers.

The first, led by Michael O’Donovan and Michael Owen of Cardiff University, United Kingdom, scanned the exomes of 617 people with schizophrenia and both their parents to find the spontaneously occurring “de novo” mutations. The second study, led by Shaun Purcell of The Broad Institute of Harvard and MIT in Cambridge, Massachusetts, and Pamela Sklar at Mount Sinai School of Medicine in New York City, took a case-control approach, looking for rare variants found more frequently in 2,536 people with schizophrenia than in 2,543 controls. Though the studies fell short of definitively pegging individual genes, they both found evidence for disruptions in sets of genes encoding the synaptic machinery that conveys glutamate signals from one neuron to another.

“We found out that the rarest, most severe point mutations—the most likely to damage a protein—contribute to schizophrenia risk,” Pamela Sklar told SRF. “But, as a group, they contribute more modestly than many thought.”

The two studies provide a sobering curative for anyone who still thought that scanning the exome in schizophrenia might quickly narrow down a few rare variants of large effect. Though the studies detected many rare variants, these were scattered across the exome, rather than piling up on certain genes. Not only does this bolster the idea that many genes contribute to schizophrenia risk, but it also emphasizes the need to do more sequencing to identify them and their effects.

This may require exome sequencing in at least 10,000 people, said Anna Need of Imperial College London, who was not involved in the study. “If you're looking for rare variants that are one in 1,000 or one in 10,000, you're not going to see many of those in a cohort of 2,500,” she added.

Rare variants have turned up in earlier forays into exome sequencing in smaller schizophrenia cohorts. One of these has been from Need and colleagues, which compared rare variants in cases and controls, and also did not support a role for a few rare variants of large effect (see SRF related news report). Previous studies of de novo mutations revealed a diverse group that rarely hit the same gene twice (see SRF related news report; SRF news report; news report; news report). This ambiguous situation, combined with the high degree of exome variation in each human being, leaves researchers straining to link rare variants to the disorder.

Many geneticists resort to gene set analysis, which asks whether variants found in schizophrenia predominately hit certain kinds of genes more than do variants found in controls. For example, one de novo study found that rare variants in the exome were enriched in genes highly expressed prenatally, when brain development is underway (see SRF related news report). The new studies both implicate sets of genes encoding parts of post-synaptic complexes that transduce glutamate signals important for information flow in the brain.

“It is reassuring that they are starting to identify these gene sets,” Need said. “But it’s not surprising that they’re not seeing gene-specific results yet because of their sample sizes.”

Sklar remains optimistic. “I'm actually really encouraged by these results,” she said. “This is genetics making big strides in building a strong foundation for understanding what’s going on. If the reality is more complicated than we expected, then understanding that is important.”

De novo notes
First author Menachem Fromer and colleagues sequenced the exomes of 617 people with schizophrenia, and each of their parents, from a Bulgarian cohort used in previous studies (see SRF related news report). This turned up 637 de novo variants within protein-coding or splice site sequences, giving a mutation rate of 1.61 x 10-8 per base per generation, which was not different from that expected in the general population. Similar to a previous study, this rate was associated with father’s age at the child's birth (see SRF related news report).

The burden of protein-altering variants—either non-synonymous ones that altered a protein’s amino acid sequence, or the loss-of-function ones that resulted in a premature stop codon, changed a splice site, or induced a frameshift—was the same in schizophrenia as in controls from other studies. When analyzed by gene, however, the researchers found what might be nascent pile-ups: Eighteen different genes were hit twice by these mutations, which was more than expected by chance (p = 0.03). Of these, two loss-of-function mutations hit TAF13, which encodes a subunit of the TFIID transcription initiation complex, and this attained genomewide significance.

The protein-altering variants found in schizophrenia also favored certain groups of genes, with significant enrichment in genes encoding parts of the activity-regulated cytoskeleton-associated scaffold protein (ARC) complex and the N-methyl-D-aspartate receptor (NMDAR) complex; for example, loss-of-function variants hit ARC complex genes 17 times more frequently in schizophrenia than those in controls. Disruptions to these complexes could disturb the process by which neural activity alters synaptic strength. Consistent with this, an enrichment in non-synonymous mutation was also found in targets of Fragile X mental retardation protein (FMRP), which also regulate synaptic plasticity.

The researchers also reported enrichment of their loss-of-function variants in genes hit by de novo mutation in autism (see SRF related news report) and intellectual disability, consistent with genetic overlaps suggested by copy number variations (Malhotra et al., 2012). People with mild cognitive impairments seemed to drive this overlap, however, which suggests that any overlaps between these disorders could reflect a shared cognitive component.

Case-control clues
In the second study, first author Shaun Purcell and colleagues sequenced the exomes of 2,536 people with schizophrenia and 2,543 controls from a Swedish sample previously studied for a genomewide association study (see SRF related news report). This raked in 635,944 coding or splice-site variants, but none of the rare ones occurred more frequently in schizophrenia than in controls. Considering different variants hitting the same gene as repeat events also did not find any schizophrenia-specific associations.

To narrow the search space (and limit corrections for multiple comparisons), the researchers focused on variants occurring in 2,546 genes, pre-selected for their suspected involvement in schizophrenia by other methods. Loss-of-function mutations in this gene set occurred more frequently in schizophrenia than in controls; for example, 1,547 of the rare variants with a frequency of <0.1 percent occurred in cases and 1,383 in controls (p = 0.0001). The mean effect of these variants, however, was not large: While 46 percent of people with schizophrenia carried at least one loss-of-function variant in the schizophrenia-related gene set, 41 percent of controls did so, giving an odds ratio of 1.12. Because this number combines the effects of multiple variants across multiple genes, it is unclear whether this reflects the watering down of a few rare variants with sizeable effects on risk, or many variants, each with a small effect.

Looking for enrichment in biologically related gene sets, the researchers found it in the ARC complex, the post-synaptic density protein-95 (PSD-95) complex, and calcium channel genes. These results reinforce the de novo findings and point to the synapse as an important locus of schizophrenia risk. Apart from the FMRP gene set, the researchers did not find much enrichment in 2,507 genes linked to autism or intellectual disability, suggesting that any genetic overlap between these disorders is limited.—Michele Solis.

Fromer et al. De novo mutations in schizophrenia implicate synaptic networks. Nature (2014) doi:10.1038/nature12929. Published online 22 January 2014. Paper

Purcell et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature (2014) doi:10.1038/nature12975. Published online 22 January 2014. Paper

Comments on News and Primary Papers
Comment by:  Francis McMahon, SRF Advisor
Submitted 23 January 2014
Posted 28 January 2014

I think these studies do represent real progress. Finding genetic support for particular pathways provides unique evidence for a causative role of these pathways in disease. Why didn't the case-control study point to individual genes? Disorders such as schizophrenia may be more like a plane crash than a typical inherited disease: Since many things can go wrong, each crash is different, but damage to key systems is very likely to lead to a bad outcome. The finding in Fromer et al. that there are 18 genes with recurrent deleterious de novo events should allow scientists to focus on these genes as especially important. The overlaps with autism and intellectual disability are interesting, though not entirely unexpected. Will we also see gene overlaps with illnesses such as bipolar disorder? It wouldn't surprise me if some of the same genes are involved, but with fewer, less deleterious hits.

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Comments on Related News

Related News: Autism Exome: Lessons for Schizophrenia?

Comment by:  Patrick Sullivan, SRF Advisor
Submitted 20 April 2012
Posted 23 April 2012
  I recommend the Primary Papers

Fascinating papers that likely presage work in the pipeline from multiple groups for schizophrenia. Truly groundbreaking work by some of the best groups in the business. Required reading for those interested in psychiatric genomics.

The identified loci provide important new windows into the neurobiology of ASD.

The results also pertain to the longstanding debate about the nature of ASD: does it result from many individually rare, Mendelian-like variants (potentially a different one in each person) and/or from the summation of the effects of many different common variants of subtle effects?

The multiple rare variant model now seems unlikely for ASD as, contrary to the expectations of some, ASD did not readily resolve into a handful of Mendelian-like diseases. (This comment is of course qualified by the limits of the technologies - which have, however, identified causal mutations for many monogenetic disorders.)

Readers might also want to read Ben Neale's comments on these papers at the Genomes Unzipped website.

View all comments by Patrick Sullivan

Related News: New Mutations Mount as Fathers Age

Comment by:  Dolores Malaspina
Submitted 27 August 2012
Posted 27 August 2012

The new report by Kong et al. (2012) demonstrates that paternal age is likely to be an important source of mutations that are relevant for schizophrenia, as we earlier hypothesized (Malaspina, 2001). Kong et al. demonstrated that the diversity in human mutation rates for offspring is dominated by the paternal age at conception. Following our initial observation that advancing paternal age was substantially associated with an increasing risk for schizophrenia, explaining a quarter of the population's attributable risk for schizophrenia (Malaspina et al., 2001), many scientists found it difficult to accept that the father’s age could be a risk pathway for schizophrenia. By contrast, the hypothesis that paternal age explained the risk for achondroplastic dwarfism achieved far greater immediate acceptance over 20 years ago (i.e., Thompson et al., 1986). While these new findings will surely advance our understanding of many de novo neuropsychiatric conditions, they also substantiate biological versus psychosocial causation theories for severe neuropsychiatric conditions.


Malaspina D. Paternal factors and schizophrenia risk: de novo mutations and imprinting. Schizophr Bull . 2001 ; 27(3):379-93. Abstract

Malaspina D, Harlap S, Fennig S, Heiman D, Nahon D, Feldman D, Susser ES. Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry . 2001 Apr ; 58(4):361-7. Abstract

Thompson JN Jr, Schaefer GB, Conley MC, Mascie-Taylor CG. Achondroplasia and parental age. N Engl J Med. 1986 Feb 20;314(8):521-2. Abstract

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Related News: New Mutations Mount as Fathers Age

Comment by:  Patrick Sullivan, SRF Advisor
Submitted 27 August 2012
Posted 27 August 2012

Kong et al. sequenced 78 pedigree clusters (mostly parent-offspring trios) to around 30x coverage. After careful quality control, they identified an average of 63 new mutations per trio. These mutations were “de novo” in that they were absent in the parents but present in an offspring and assumed to have occurred during gametogenesis.

Intriguingly, more of these mutations occurred in older parents. The authors present several lines of evidence to implicate fathers rather than mothers, and estimated that there were about two extra de novo mutations per year of increase in paternal age. This conclusion is consistent with several of the exome sequencing papers published in Nature a few months ago.

Increased paternal age is an epidemiological risk factor for schizophrenia and autism, with relative risks on the order of two and five, respectively. This paper suggests a potential mechanism for the paternal age effect that might eventually prove to be relevant for some fraction of cases.

It is important to note that advanced paternal age is a risk factor, not a determining feature. Risk is increased, but not in a deterministic manner.

View all comments by Patrick Sullivan

Related News: New Mutations Mount as Fathers Age

Comment by:  John McGrath, SRF Advisor
Submitted 28 August 2012
Posted 28 August 2012
  I recommend the Primary Papers

In 2001, Dolores Malaspina alerted the research community to the link between advanced paternal age and increased risk of schizophrenia—she suggested that this may be due to de novo mutations in the male germ line (Malaspina et al., 2001). The study BY Kong et al. provides compelling evidence in support of this hypothesis (Kong et al., 2012). A related paper in Nature Genetics also demonstrates an association between paternal age and changes in microsatellite properties across generations (Sun et al., 2012).

While the hypothesis that de novo mutations accumulate due to copy error mutations in the production of germ cells in older males is compelling, it is still possible (albeit unlikely) that this association may be due to unmeasured confounding. For example, older men might be exposed to more environmental toxins that accumulate over time and subsequently cause mutations in the offspring of older dads as a byproduct of the greater exposure. There is also the evidence from Denmark indicating that, when adjusted for age of first child, the association between paternal age and risk of schizophrenia fades out (Petersen et al., 2011). This finding suggests that selective factors may also operate (e.g., perhaps related to personality of schizotypal men, etc.).

However, animal experiments can provide useful clues to this puzzle (Foldi et al., 2011). Mouse models of advanced paternal age indicate that the offspring of older sires differ from control animals on behavior and brain structure (Smith et al., 2009; Foldi et al., 2010). Of particular relevance for the study by Kong et al., a mouse experiment found that the offspring of older sires were significantly more likely to have de novo copy number variants (Flatscher-Bader et al., 2011).

We now have convergent evidence from risk factor epidemiology, animal experiments, and genetic studies. The evidence supports an increased risk of schizophrenia in the offspring of older fathers, and points to age-related mutagenesis in the male germ cell. It is still not clear why these age-related events seem to differentially impact on neurodevelopmental disorders (e.g., autism is also linked to paternal age). Perhaps neocortical development is less well "buffered" (compared to more phylogenetically ancient organs); thus, de novo mutations can more readily "decanalize" certain features of brain development (McGrath et al., 2011). From an evolutionary developmental biology perspective (evo-devo), the dictum goes “Last in, first to break.”

It is rare that different fields of research converge in such an obedient fashion. It is time that we pause and reflect on this important milestone—and also offer a rousing “three cheers for Dolores Malapsina!”


Flatscher-Bader T, Foldi CJ, Chong S, Whitelaw E, Moser RJ, Burne TH, Eyles DW, McGrath JJ. Increased de novo copy number variants in the offspring of older males. Transl Psychiatry. 2011 Aug 30;1:e34. Abstract

Foldi CJ, Eyles DW, McGrath JJ, Burne TH. Advanced paternal age is associated with alterations in discrete behavioural domains and cortical neuroanatomy of C57BL/6J mice. Eur J Neurosci. 2010 Feb;31(3):556-64. Abstract Foldi CJ, Eyles DW, Flatscher-Bader T, McGrath JJ, Burne TH. New perspectives on rodent models of advanced paternal age: relevance to autism. Front Behav Neurosci . 2011 ; 5():32. Abstract

Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P, Magnusson G, Gudjonsson SA, Sigurdsson A, Jonasdottir A, Jonasdottir A, Wong WS, Sigurdsson G, Walters GB, Steinberg S, Helgason H, Thorleifsson G, Gudbjartsson DF, Helgason A, Magnusson OT, Thorsteinsdottir U, Stefansson K. Rate of de novo mutations and the importance of father's age to disease risk. Nature. 2012 Aug 23;488(7412):471-5. Abstract

Malaspina D, Harlap S, Fennig S, Heiman D, Nahon D, Feldman D, Susser ES. Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry. 2001 Apr ; 58(4):361-7. Abstract

McGrath JJ, Hannan AJ, Gibson G. Decanalization, brain development and risk of schizophrenia. Transl Psychiatry. Abstract

Petersen L, Mortensen PB, Pedersen CB. Paternal age at birth of first child and risk of schizophrenia. Am J Psychiatry. 2011 Jan;168(1):82-8. Abstract

Smith RG, Kember RL, Mill J, Fernandes C, Schalkwyk LC, Buxbaum JD, Reichenberg A. Advancing paternal age is associated with deficits in social and exploratory behaviors in the offspring: a mouse model. PLoS One. 2009 Dec 30;4(12):e8456. Abstract

Sun JX, Helgason A, Masson G, Ebenesersdóttir SS, Li H, Mallick S, Gnerre S, Patterson N, Kong A, Reich D, Stefansson K. A direct characterization of human mutation based on microsatellites. Nat Genet. 2012 Aug 23. Abstract

View all comments by John McGrath

Related News: New Mutations Mount as Fathers Age

Comment by:  Georg Winterer (Disclosure)
Submitted 28 August 2012
Posted 28 August 2012
  I recommend the Primary Papers

Just a few thoughts:

One question is whether it is just age per se that produces de novo mutations or an accumulation of environmental effects like drug abuse, alcohol, or other potentially harmful toxic environments, etc. What I also would like to know is whether it is the number of sperm cycles; in that case, men who are sexually more active should have a greater risk to produce more de novo mutations.

View all comments by Georg Winterer

Related News: New Mutations Mount as Fathers Age

Comment by:  Michael O'Donovan, SRF AdvisorGeorge Kirov
Submitted 31 August 2012
Posted 31 August 2012

In a genomic sequencing study of 78 parent-proband trios (21 probands with schizophrenia, 44 with autism spectrum disorder [ASD]), Kong and colleagues (2012) identify almost 5,000 DNA single base changes that occurred as a result of new mutations. For five of the trios, the proband had a child who was also sequenced, and in this subset with three generations of data, Kong and colleagues were able to determine if the mutations had arisen on the paternal or maternal chromosomes. Although this subsample was small, paternal chromosomes showed much greater variance in the number of mutations than maternal chromosomes, suggesting that paternal variables are more relevant to variance in the overall de novo mutation rate than maternal variables. In the larger sample as a whole, although the parental origin of the mutations could not be determined, the number of new mutations carried by an individual could be almost completely explained by a combination of random variation and paternal age. Models of linear and of exponential increases in the number of mutations by paternal age both described the data well, the ability to distinguish between the two being constrained by a lack of fathers at the higher age. Children of fathers aged 40 had approximately twice the number of mutations as those aged 20. After accounting for random variation and paternal age, in this sample, there was very little residual variation to be explained by other factors, including maternal age and within-population environmental exposures. A possible impact of cross-population environmental exposures was not addressed, since all the subjects came from Iceland.

Overall, the findings from what is yet another impressive paper from the deCODE group support the proposition that paternal age is an important factor in determining the probability that a child might inherit a new mutation (see Goriely and Wilkie, 2012, for a wider discussion of earlier data on paternal age and mutation rates, particularly in sperm) and additionally quantify this effect in the context of other possible unexplained variables.

This is clearly an important paper for understanding factors dictating the rate by which new mutations occur, and is therefore a paper that will have wide relevance to diseases to which such mutations make a substantial contribution. But from the perspective of most readers of this Forum, it is more important to note what the study is not about.

There is good evidence that risk of schizophrenia increases with paternal age (Malaspina et al., 2001; Zammit et al., 2003; Frans et al., 2011). This is certainly compatible with the involvement of new mutations of the sort described in the paper by Kong and colleagues, but there are several alternative explanations. For example, fathers with high trait liability for schizophrenia might have subclinical characteristics making them less effective at reproduction (e.g., they may find it more difficult to find a partner) and, as a result, elderly fathers might be enriched for transmissible schizophrenia alleles. Consistent with this (and other explanations not dependent on new mutations), one large Danish study found that the paternal age effect was best explained by age at which fathers first reproduce, not the age (which is more relevant to new mutations) when the affected offspring was conceived (Petersen et al., 2011). Of general importance as it is, the study by Kong and colleagues makes no contribution to resolving to what extent the paternal age effect observed in schizophrenia (and autism) is explained by new mutations, or indeed to what extent new mutations are involved in these disorders at all. Indeed, as the authors point out, the fact that they have studied probands, the majority of whom are affected by schizophrenia or ASD, is an irrelevance; essentially identical findings would be expected if they had studied other types of families. This is because the average proband carries over 60 de novo mutations, of which, even under an extreme model in which all schizophrenia is caused by de novo mutations, at most, one or two (if any) might be schizophrenia or ASD relevant. Consequently, de novo mutations related to the phenotype of the proband cannot substantially contribute to the overall pattern of results.

Overall, this study provides empirical evidence for a mechanism by which some of the paternal age effects might be explained by de novo point mutations, but it is worth stressing that the fact that the authors have studied schizophrenia and ASD is incidental, and this study does not address the extent by which, if at all, mutations of this type make any contribution to schizophrenia (or autism). Finally, since the results of this paper have been widely reported (at least in the UK), we think it is important to note for the general reader that, while the paternal age effect of risk of schizophrenia (and autism) seems to be real, the vast majority of people with schizophrenia are not born to elderly fathers. More importantly, since the causal direction of the paternal age effect on schizophrenia risk is unknown, there is currently no strong reason to urge potential fathers to consider earlier reproduction as a strategy for reducing risk of this particular disorder.


Zammit S, Allebeck P, Dalman C, Lundberg I, Hemmingson T, Owen MJ, Lewis G. Paternal age and risk for schizophrenia. Br J Psychiatry. 2003 Nov;183:405-8. Abstract

Malaspina D, Harlap S, Fennig S, Heiman D, Nahon D, Feldman D, Susser ES. Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry. 2001 Apr;58(4):361-7. Abstract

Goriely A, Wilkie AO. Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease. Am J Hum Genet. 2012 Feb 10;90(2):175-200. Review. Abstract

Frans EM, McGrath JJ, Sandin S, Lichtenstein P, Reichenberg A, Långström N, Hultman CM. Advanced paternal and grandpaternal age and schizophrenia: a three-generation perspective. Schizophr Res. 2011 Dec;133(1-3):120-4. Epub 2011 Oct 14. Abstract

Petersen L, Mortensen PB, Pedersen CB. Paternal age at birth of first child and risk of schizophrenia. Am J Psychiatry. 2011 Jan;168(1):82-8. Epub 2010 Oct 15. Abstract

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Related News: New Mutations Mount as Fathers Age

Comment by:  Bernard Crespi
Submitted 3 September 2012
Posted 5 September 2012
  I recommend the Primary Papers

Kong et al. (2012) is an outstanding paper that provides the first detailed quantification of how human de novo mutations in sperm and eggs vary with parental age. The paper and its aftermath provide a number of important lessons for researchers studying neurodevelopmental disorders and parental age:

1. The work demonstrates directly that CpG dinucleotides contribute the lion's share of new mutations. CpG sites are of particular interest in understanding effects of de novo mutations because they differentially create new transcription factor binding sites (Zemojtel et al., 2011), as well as mediate the effects of methylation and genomic imprinting. Such findings might help to focus efforts at interpreting the functional importance of the myriad de novo variants that pepper each genome.

2. The work generates an apparent paradox: if, as the authors claim, paternal age so strongly predominates over maternal age in its de novo mutational effects, why do so many parental-age studies of autism and schizophrenia show clear effects of maternal age as well (e.g., Lopez-Castroman et al., 2010; Parner et al., 2012; Rahbar et al., 2012; Sandin et al., 2012)? Might maternal-age effects be mediated by different processes?

3. The X chromosome was not included in the analysis, despite its expected contribution to de novo mutational effects being much stronger than for autosomes, due to its hemizygosity (as found, e.g., in intellectual disability). A recent study also strikingly implicates the X chromosome in psychosis risk, perhaps involving epigenetic mechanisms (Goldstein et al., 2011).

4. It is important to avoid neurodevelopmental tunnel vision with regard to parental age effects. Advanced maternal age, for example, has been documented as a risk factor for a suite of other conditions, including hypertension, diabetes, cancer, and Alzheimer's (for a review, see Myrskylä and Fenelon, 2012), as expected if it exerts effects on all polygenic conditions.

5. As anyone following popular media accounts will have noticed, the paper has been fundamentally misinterpreted in translation from the scientific to popular literature. Contrary to almost all reports in the popular press (including, e.g., The New York Times), the paper clearly does not show that higher paternal age is associated with mutations that increase the risk of autism or schizophrenia. As noted by other commentators, to do so would require that the authors link paternal age with the number of new mutations that are actually known to contribute to autism or schizophrenia. This muddle should caution authors to be as clear in explaining what their findings do not show as they are in explaining what they actually demonstrate. If subsequent work shows that age-dependent point mutations themselves do not mediate increased autism or schizophrenia risk, scientific credibility will unjustifiably suffer.

6. Finally, the press has jumped on advanced parental age as an important possible factor in the increased diagnoses of autism over the past 30 or so years. But if increased mutation load has increased rates of autism, why haven't rates of schizophrenia increased in lockstep, albeit with a 20-year delay?

Parental age has been suspected as an important factor in genetically based, de novo conditions since Weinberg (of Hardy-Weinberg fame) noticed in 1912 that children with achondroplasia (a form of dwarfism) were later-born in sibships. One hundred years later, we are one large step closer to understanding why. Let us help to ensure that this step is free of de novo errors of interpretation and implication, and move forward with speed.


Goldstein JM, Cherkerzian S, Seidman LJ, Petryshen TL, Fitzmaurice G, Tsuang MT, Buka SL. Sex-specific rates of transmission of psychosis in the New England high-risk family study. Schizophr Res. 2011 May;128(1-3):150-5. Abstract

Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P, Magnusson G, Gudjonsson SA, Sigurdsson A, Jonasdottir A, Jonasdottir A, Wong WS, Sigurdsson G, Walters GB, Steinberg S, Helgason H, Thorleifsson G, Gudbjartsson DF, Helgason A, Magnusson OT, Thorsteinsdottir U, Stefansson K. Rate of de novo mutations and the importance of father's age to disease risk. Nature. 2012 Aug 22; 488: 471-5. Abstract

Lopez-Castroman J, Gómez DD, Belloso JJ, Fernandez-Navarro P, Perez-Rodriguez MM, Villamor IB, Navarrete FF, Ginestar CM, Currier D, Torres MR, Navio-Acosta M, Saiz-Ruiz J, Jimenez-Arriero MA, Baca-Garcia E. Differences in maternal and paternal age between schizophrenia and other psychiatric disorders. Schizophr Res. 2010 Feb;116(2-3):184-90. Abstract

Myrskylä M, Fenelon A. Maternal Age and Offspring Adult Health: Evidence From the Health and Retirement Study. Demography . 2012 Aug 28. Abstract

Parner ET, Baron-Cohen S, Lauritsen MB, Jørgensen M, Schieve LA, Yeargin-Allsopp M, Obel C. Parental age and autism spectrum disorders. Ann Epidemiol. 2012 Mar;22(3):143-50. Abstract

Rahbar MH, Samms-Vaughan M, Loveland KA, Pearson DA, Bressler J, Chen Z, Ardjomand-Hessabi M, Shakespeare-Pellington S, Grove ML, Beecher C, Bloom K, Boerwinkle E. Maternal and Paternal Age are Jointly Associated with Childhood Autism in Jamaica. J Autism Dev Disord. 2012 Sep;42(9):1928-38. Abstract

Sandin S, Hultman CM, Kolevzon A, Gross R, MacCabe JH, Reichenberg A. Advancing maternal age is associated with increasing risk for autism: a review and meta-analysis. J Am Acad Child Adolesc Psychiatry. 2012 May;51(5):477-486.e1. Abstract

Zemojtel T, Kielbasa SM, Arndt PF, Behrens S, Bourque G, Vingron M. CpG deamination creates transcription factor-binding sites with high efficiency. Genome Biol Evol. 2011;3:1304-11. Abstract

View all comments by Bernard Crespi

Related News: Exome Sequencing Hints at Prenatal Genes in Schizophrenia

Comment by:  Sven CichonMarcella RietschelMarkus M. Nöthen
Submitted 5 October 2012
Posted 5 October 2012

The new exome sequencing study by Xu et al. confirms previous results by the same research group (Xu et al., 2011) and by an independent group (Girard et al., 2011) that a significantly higher frequency of protein-altering de novo single nucleotide variants (SNVs) and in/dels is found in sporadic patients with schizophrenia. It is certainly reassuring that this observation has now been confirmed in an independent and considerably larger sample (134 patient-parent trios and 34 control-parent trios).

A closer look also reveals differences between this study and the study by Girard et al.: Xu et al. do not find a significantly higher overall de novo mutation rate per base per generation when comparing schizophrenia and control trios (1.73 x 10-08 vs. 1.28 x 10-08). In contrast, the Girard study found 2.59 x 10-08 de novo mutations in schizophrenia trios as opposed to the 1.1 x 10-08 events reported in the general population by the 1000 Genomes Project. The larger sample size in the new study by Xu et al., however, suggests that their estimation of the de novo mutation rates may be more precise now.

What eventually seems to count is the quality of the de novo mutations in the sporadic schizophrenia patients. The function of the genes hit by the non-synonymous/deleterious (as defined by in-silico scores) mutations is diverse and shows similarity with functions reported for common risk genes for schizophrenia identified by GWAS. Interestingly, there is an overrepresentation of genes that are predominantly expressed during embryogenesis, strongly highlighting a possible effect of neurodevelopmental disturbances in the etiology of schizophrenia (and nicely supporting what has already been concluded from GWAS).

It would probably be very interesting to estimate the penetrance of such de novo mutations to get a feeling for their individual impact on the development of the disease. In the absence of a reasonable number of individuals with the same mutation, however, this will be a difficult task.

Another aspect that is missing in the current paper, but is accessible to investigation, is the frequency/quality of de novo mutations in trios with a family history of schizophrenia and comparison to the figures seen in the sporadic trios. That might (or might not) support the authors’ conclusion that de novo events play a strong role in sporadic cases (and not in familial cases).


Xu B, Roos JL, Dexheimer P, Boone B, Plummer B, Levy S, Gogos JA, Karayiorgou M. Exome sequencing supports a de novo mutational paradigm for schizophrenia. Nat Genet . 2011 Sep ; 43(9):864-8. Abstract

Girard SL, Gauthier J, Noreau A, Xiong L, Zhou S, Jouan L, Dionne-Laporte A, Spiegelman D, Henrion E, Diallo O, Thibodeau P, Bachand I, Bao JY, Tong AH, Lin CH, Millet B, Jaafari N, Joober R, Dion PA, Lok S, Krebs MO, Rouleau GA. Increased exonic de novo mutation rate in individuals with schizophrenia. Nat Genet . 2011 Sep ; 43(9):860-3. Abstract

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Related News: Exome Sequencing Hints at Prenatal Genes in Schizophrenia

Comment by:  Patrick Sullivan, SRF Advisor
Submitted 5 October 2012
Posted 5 October 2012

This paper by the productive group at Columbia increases our knowledge of the role of rare exon mutations in schizophrenia. The authors applied exome sequencing—a newish high-throughput sequencing technology—to trios consisting of both parents plus an offspring with schizophrenia. The authors focused on a subset of the genome (the “exome,” genetic regions believed to code for protein) on a subset of genetic variants (SNPs and insertion/deletion variants) of predicted functional significance, and on one type of inheritance (“de novo“ mutations, those absent in both parents and present in the offspring with schizophrenia).

The sample sizes are the largest yet reported for schizophrenia—231 affected trios and 34 controls. About 28 percent of these samples were reported in 2011 (Xu et al., 2011). A recent schizophrenia sequencing study (N = 166) from the Duke group was unrevealing (Need et al., 2012). The numbers in the Xu, 2012 paper are small compared to the three Nature trio studies for autism (see SRF related news story), an approximately threefold larger trio study for schizophrenia (in preparation), a case-control exome sequencing study for schizophrenia (total N ~5,000, in preparation), and a case-control exome chip study for schizophrenia (total N ~11,000, in preparation).

The authors reported:

more mutations with older fathers, as has been reported before (see SRF related news story). Note that advanced paternal age is an established risk factor for schizophrenia.

more de novo/predicted functional/exonic mutations in schizophrenia than in controls. However, the difference was slight, one-sided P = 0.03. One can quibble with the use of a one-tailed test (should never be used, in my opinion), but it is difficult to interpret this result unless paternal age is included as a covariate in this critical test.

an impressive set of bioinformatic and integrative analyses—see the paper for the large amount of work they did.

as might be predicted given the small sample size and the rarity of these sorts of mutations, there was no statistically significant pile-up of variants in specific genes. Hence, to my reading, the authors do not compellingly implicate any specific genes in the pathophysiology of schizophrenia. This conclusion is consistent with Need et al., 2012, and I note that the autism work implicated only a few genes (e.g., CHD8 and KATNAL2).

Note that the authors would disagree with the above, as they chose to focus on a set of genes that they thought stood out (reporting an aggregate P of 0.002), and the last third of the paper focuses on these genes. However, the human genetics community now insists on two critical points for implicating specific genes in associations with a disorder. The first is statistical significance, and the critical P value for an exome sequencing study is on the order of 1E-6. The second is replication. In my view, neither of these standards are achieved. However, their observations are intriguing, and may well eventually move us forward.

The key observation in this paper is the increased rate of de novo variation in schizophrenia cases. Is the increased rate indeed part of an etiological process? In other words, older fathers have an increased chance of exonic mutations, and these, in turn, increase risk for schizophrenia? Or are these merely hitch-hikers of no particularly biological import?

A major issue with exome studies is that there are so many predicted functional variants in apparently normal people. We all carry on the order of 100 exonic variants of predicted functional consequences with on the order of 20 genes that are probable knockouts. If part of the risk for schizophrenia indeed resides in the exome, very large studies will be required to identify such loci confidently. Moreover, published work on autism and unpublished work for type 2 diabetes, coronary artery disease, and schizophrenia suggest that this will require very large sample sizes, on the order of 100 times more than reported here. And, it is possible that the exome is not all that important for schizophrenia.


Xu B, Roos JL, Dexheimer P, Boone B, Plummer B, Levy S, Gogos JA, Karayiorgou M. Exome sequencing supports a de novo mutational paradigm for schizophrenia. Nat Genet . 2011 Sep ; 43(9):864-8. Abstract

Need AC, McEvoy JP, Gennarelli M, Heinzen EL, Ge D, Maia JM, Shianna KV, He M, Cirulli ET, Gumbs CE, Zhao Q, Campbell CR, Hong L, Rosenquist P, Putkonen A, Hallikainen T, Repo-Tiihonen E, Tiihonen J, Levy DL, Meltzer HY, Goldstein DB. Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia. Am J Hum Genet . 2012 Aug 10 ; 91(2):303-12. Abstract

View all comments by Patrick Sullivan

Related News: Ambitious Genetic Integration Analysis of Schizophrenia Points to Early Brain Development

Comment by:  Roger Boshes
Submitted 10 August 2013
Posted 20 August 2013

These data suggest a "stem" circuit that may be common to many patients with schizophrenia, but subsequent de novo mutations may explain the protean manifestations of the disorder. Alternatively, this prefrontal perturbation may be related to a heritable, i.e., not a somatic, mutation that explains 80 percent heritability but not the protean phenotypic expression of the condition. Finally, it may be the link between schizophrenia and some flavors of autism.


Boshes RA, Manschreck TC, Konigsberg W. Genetics of the schizophrenias: a model accounting for their persistence and myriad phenotypes. Harv Rev Psychiatry. 2012 May-Jun; 20(3):119-29. Abstract

View all comments by Roger Boshes

Related News: Bigger Schizophrenia GWAS Yields More Hits

Comment by:  Sven Cichon
Submitted 30 August 2013
Posted 30 August 2013

This paper is an important addition to the psychiatric genetics literature. One important message of it is that increasing the GWAS sample size in a complex neuropsychiatric phenotype such as schizophrenia identifies more common risk loci.

In the first-wave schizophrenia mega-analysis two years ago (Schizophrenia Psychiatric Genome-Wide Association Study Consortium, 2011), five risk loci at genomewide significance were detected, and it was speculated that more would follow with larger sample sizes. In fact, by performing a meta-analysis of a new Swedish schizophrenia sample (about 5,000 patients and 6,000 controls) and the first-wave PGC sample (about 9,000 patients and 12,000 controls) plus follow-up/replication in large, independent samples, the authors now find 22 genomic loci at genomewide significance. This is another important step forward in schizophrenia genetics.

It is reassuring (and important for the scientific community to know) that there is support for some of the previously reported loci. As expected, the findings are getting much more consistent now with the increasing power of the samples. Interestingly, some loci pop up now at genomewide significance that were known from bipolar disorder or combined phenotype analyses (schizophrenia + bipolar), such as CACNA1C and CACNB2. Together with the finding that there is an enrichment of smaller p values in genes encoding calcium channel subunits, there is now growing evidence that calcium signaling is involved in both bipolar disorder and schizophrenia. Calcium signaling is a crucial neuronal process and relevant in a number of human diseases, as the authors nicely review. Importantly, calcium channel complexes may be useful for clinical translation (e.g., as drug targets).

Variation in another gene that was implicated in bipolar disorder before, NCAN, was found at genomewide significance in schizophrenia in the study by Ripke et al. (in fact, an association with schizophrenia was already reported earlier by Mühleisen et al., 2012). It seems that another "theme" of disease-relevant genes may be neurodevelopmental effects in both bipolar disorder and schizophrenia. The different lincRNAs implicated now among the 22 genomewide significant findings may also point in this direction.

What I find particularly interesting are the considerations regarding the much debated genetic architecture of schizophrenia. The authors’ simulations, although certainly still not perfectly exact, substantiate previous calculations that common SNPs make substantial contributions to the risk for schizophrenia.

To my knowledge, for the first time there are estimates regarding the absolute number of common SNPs that contribute to the etiology of schizophrenia: The authors estimate "6,300 to 10,200 independent and mostly common SNPs." While it is difficult to deduce the number of genes or functional units covered by these SNPs, several thousand are well possible. Many of these loci/genes will fall into the same biological pathways, and the identification of a subset of these will probably suffice to identify the most important biological processes. The authors estimate that the top 2,000 loci might be sufficient, and maybe it is even fewer. At the same time, they estimate that such a number of identified loci is not completely out of reach. Sixty thousand patients and 60,000 controls should have enough statistical power to identify between 400 and 1,100 common loci at genomewide significance. Psychiatrists will agree that a great collaborative effort will be required to recruit such a large number of patients. But it is not impossible. The next wave of the PGC schizophrenia group is already moving in this direction.


Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium (2011) Genome-wide association study identifies five new schizophrenia loci. Nat Genet. 43:969-76. Abstract

Mühleisen TW, Mattheisen M, Strohmaier J, et al. (2012) Association between schizophrenia and common variation in neurocan (NCAN), a genetic risk factor for bipolar disorder. Schizophr Res. 138:69-73. Abstract

View all comments by Sven Cichon

Related News: Bigger Schizophrenia GWAS Yields More Hits

Comment by:  Ole A. Andreassen, SRF AdvisorMartin Tesli
Submitted 6 October 2013
Posted 7 October 2013
  I recommend the Primary Papers

The recent genomewide association study (GWAS) by Ripke and co-workers is a very important contribution to our knowledge of the genetic underpinnings of schizophrenia. By adding ~5,000 schizophrenia cases and ~6,000 healthy controls from Sweden to the Psychiatric Genomics Consortium (PGC) results from 2011 (PGC, 2011), the authors identified 22 gene loci (including 13 novel) at genomewide significance. These findings confirm that previous schizophrenia GWAS have been statistically underpowered, and that increasing the sample size is a successful approach to bridge the gap between the high heritability estimates in schizophrenia and low variance explained by currently identified genetic variants.

With increasing sample size, consistency is also enhanced. Reassuringly, of the 100 most significant SNPs in the Sweden/PGC meta-analysis, 90 percent had the same sign. Moreover, previously reported signals from immune-related genes in the MHC region on chromosome 6 were confirmed, as well as genes encoding calcium channel subunits, miR-137, and targets of miR-137. Additionally, the authors found enrichment in an extended set of genes with predicted miR-137 target sites. The results also pointed to long intergenic noncoding RNAs (lincRNAs), as 13 out of 22 identified regions contain lincRNAs. Interestingly, there is evidence that lincRNAs have functions related to epigenetic regulation.

Using two newly developed methods—genomewide complex trait analysis (GCTA) and applied Bayesian polygenic analysis (ABPA)—the authors estimated that common variants account for 52 percent and 78 percent, respectively, of the phenotypic variation in schizophrenia. These numbers are, although imprecisely, in accordance with the high heritability estimates from meta-analyses on twin studies (81 percent) (Sullivan et al., 2003) and large epidemiological studies (64 percent) (Lichtenstein et al., 2009), and indicate that a substantial proportion of the genetic risk for schizophrenia can be explained by common variants identified in GWAS. With the ABPA method, the authors also estimated that between 6,300 and 10,200 SNPs explain 50 percent of the variance in schizophrenia susceptibility. This clearly shows the high polygenicity in schizophrenia.

The authors suggest that 60,000 schizophrenia cases and 60,000 controls are warranted to identify ~800 markers at genomewide significance level. With the combined effort from the PGC, this might be achievable, and a larger proportion of the hidden heritability will undoubtedly be revealed. However, when using the PGC schizophrenia sample as the discovery set and the Swedish sample as the test set, explained variance (Nagelkerke pseudo R2) was only ~0.06 (contrasted by an impressive significance level of 2 x 10-114). This is slightly disappointing, as the explained variance with similar methodology was found to be ~0.03 in a study by Purcell and co-workers in 2009 (Purcell et al., 2009). By increasing the sample size five times (~6,000 vs. ~30,000 individuals), explained variance has only increased from 3 to 6 percent. Although a further increase in the PGC sample will provide important information on risk variants, a refinement of the method is probably also needed to discover larger parts of the hidden heritability for the highly polygenic disorder schizophrenia. Such methods might include Bayesian models for weighing SNPs based on prior evidence, for example, related to pleiotropic effects (Andreassen et al., 2013) and genic annotation (Schork et al., 2013). A combination of large numbers and methodological refinement might prove particularly potent, both in terms of explaining more of the variance and identifying underlying molecular pathways.


PGC. Genome-wide association study identifies five new schizophrenia loci. Nat Genet . 2011 Oct ; 43(10):969-76. Abstract

Andreassen OA, Thompson WK, Schork AJ, Ripke S, Mattingsdal M, Kelsoe JR, Kendler KS, O'Donovan MC, Rujescu D, Werge T, Sklar P, , , Roddey JC, Chen CH, McEvoy L, Desikan RS, Djurovic S, Dale AM. Improved detection of common variants associated with schizophrenia and bipolar disorder using pleiotropy-informed conditional false discovery rate. PLoS Genet . 2013 Apr ; 9(4):e1003455. Abstract

Lichtenstein P, Yip BH, Björk C, Pawitan Y, Cannon TD, Sullivan PF, Hultman CM. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet . 2009 Jan 17 ; 373(9659):234-9. Abstract

Purcell SM, Wray NR, Stone JL, Visscher PM, O'Donovan MC, Sullivan PF, Sklar P. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature . 2009 Aug 6 ; 460(7256):748-52. Abstract

Schork AJ, Thompson WK, Pham P, Torkamani A, Roddey JC, Sullivan PF, Kelsoe JR, O'Donovan MC, Furberg H, Schork NJ, Andreassen OA, Dale AM. All SNPs are not created equal: genome-wide association studies reveal a consistent pattern of enrichment among functionally annotated SNPs. PLoS Genet . 2013 Apr ; 9(4):e1003449. Abstract

Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry . 2003 Dec ; 60(12):1187-92. Abstract

View all comments by Ole A. Andreassen
View all comments by Martin Tesli

Related News: Channels of Working Memory

Comment by:  David C. Glahn
Submitted 11 March 2014
Posted 11 March 2014

The article by Heck and colleagues provides additional support for the notion that common genetic factors influence risk for schizophrenia and working memory performance. While evidence that working memory performance is sensitive to genetic liability for schizophrenia was well established by twin and family studies (e.g., Cannon et al., 2000; Glahn et al., 2007), the current article extends these findings by suggesting that at least a portion of this joint effect is conferred by common variants in the voltage-gated cation channel activity (see QuickGO page) gene network. The paper provides a potential biological mechanism through which a set of genes could influence both traits. Such testable biological hypotheses are critical both for unraveling the genetic architecture of schizophrenia and other psychotic illnesses and for helping to characterize how these genes aid in manifesting the behavioral disorders. Thus, although the paper does not provide a single pleiotropic gene as would be required in classical human genetics, I believe the findings represent a true advancement in our understanding of schizophrenia genetics.

A major strength of the paper is the large number of independent samples with similar, but not identical, working memory measures that provided data for the discovery or replication samples. Papassotiropoulos and his group have applied this powerful approach to provide insight into the genetic make-up of cognitive processes, particularly memory.

Recently, there has been a good deal of debate concerning the utility of endophenotypes in the search for mental illness genes. As described by Gottesman and Gould (Gottesman and Gould, 2003), endophenotypes are measurable components unseen by the unaided eye along the pathway between disease and distal genotype. John Blangero and I pointed out that joint genetic determination (pleiotropy) of endophenotype and disease risk is fundamental to the endophenotype concept (Glahn et al., 2012). The current paper clearly demonstrates pleiotropy between schizophrenia risk and working memory performance, reinforcing working memory as a schizophrenia endophenotype and demonstrating how such traits can be used to provide testable biological hypotheses.

Finally, I would like to point out that this work was primarily conducted in healthy individuals not selected for mental illness. The endophenotype and normal variation strategy (e.g., using unselected samples to learn about the genetic factors influencing an endophenotype and then confirming these results in a sample selected for the illness) has worked in other areas of medicine, and I believe it will work in psychiatric genetics as well. Indeed, I think this paper demonstrated exactly that.


Cannon TD, Huttunen MO, Lonnqvist J, Tuulio-Henriksson A, Pirkola T, Glahn D, Finkelstein J, Hietanen M, Kaprio J, Koskenvuo M. The inheritance of neuropsychological dysfunction in twins discordant for schizophrenia. Am J Hum Genet. 2000 Aug;67(2):369-82. Epub 2000 Jul 3. Abstract

Glahn DC, Almasy L, Blangero J, Burk GM, Estrada J, Peralta JM, Meyenberg N, Castro MP, Barrett J, Nicolini H, Raventós H, Escamilla MA. Adjudicating neurocognitive endophenotypes for schizophrenia. Am J Med Genet B Neuropsychiatr Genet. 2007 Mar 5;144B(2):242-9. Abstract

Glahn DC, Curran JE, Winkler AM, Carless MA, Kent JW Jr, Charlesworth JC, Johnson MP, Göring HH, Cole SA, Dyer TD, Moses EK, Olvera RL, Kochunov P, Duggirala R, Fox PT, Almasy L, Blangero J. High dimensional endophenotype ranking in the search for major depression risk genes. Biol Psychiatry. 2012 Jan 1;71(1):6-14. Abstract

Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003 Apr;160(4):636-45. Review. Abstract

View all comments by David C. Glahn

Related News: Bigger Schizophrenia GWAS Reports More Than 100 Hits

Comment by:  David GoldmanColin Hodgkinson
Submitted 20 July 2014
Posted 21 July 2014

The fact that schizophrenia is moderately to highly heritable is yesterday’s news; however, this genetic study, because of its large magnitude and with >100 genome-wide significant loci, is a watershed event in the discovery of the genetic variation that must be responsible for this inheritance. There are limitations. The principal limitation is that not one of the findings reported in this paper meets the standard demanded in medical genetics. As reviewed by Flint and Munafo, and following the emphasis of the paper, the focus is on the statistical findings rather than the identification and validation of any one of the >100 genome-wide significant loci at the level of the functional nucleotide difference and how that translates into behavior.

In fact, the principle finding of this study is that no common coding sequence variant accounts for any large fraction of the genetic liability to schizophrenia. It is interesting to speculate on the nature of the genetic variation that causes schizophrenia based on the loci discovered here, which are responsible for an important but still small part of that genetic liability. However, the conclusion that the variants are regulatory in nature will have to await a more complete accounting of the genes and loci involved, and the actual identification of the loci responsible. This is different than pointing to significant associations to SNPs outside of coding regions and to lack of associations to SNPs within coding regions.

Despite the cold water thrown on the eight hundred candidate genes previously implicated in schizophrenia, all of which Flint and Munafo label as “of dubious value,” it is actually critically important that more than a few were among the genome-wide significant loci. Otherwise, and for example if genetic variation at no dopamine or glutamate gene was found to be important, one might doubt the validity of this study. We shouldn’t aggregate or characterize the other association results as if we really understand them or know why they did not generate signals in this genome-wide association study. Clearly some are false positives. Some involve VNTR loci that are not even captured by SNP arrays. Some may be valid in particular populations but not others where the functional variant is absent. Some may depend on the study of particular phenotypes that are not the schizophrenia diagnosis itself but are associated with the disease (for example COMT and cognitive phenotypes) or that can be conflated with schizophrenia (for example DISC1 and schizoaffective disorder).

This genome-wide association study is a starting point for studies on more than 100 genes to elucidate their roles in schizophrenia but it is also a challenge to all of us interested in the biology of schizophrenia. It is best to keep an open mind about the genes involved in schizophrenia and the types of alleles at these genes until some of those functional alleles have been verified.

View all comments by David Goldman
View all comments by Colin Hodgkinson

Related News: Bigger Schizophrenia GWAS Reports More Than 100 Hits

Comment by:  Francis McMahon, SRF Advisor
Submitted 22 July 2014
Posted 22 July 2014

Those of us who attended the annual meeting of the International Society of Psychiatric Genetics in Boston last October were electrified by the striking findings of the Psychiatric Genomics Consortium, reporting over a hundred genome-wide significant genetic marker associations in the largest ever genome-wide association study of schizophrenia. After what seemed like a long wait, this landmark work has now appeared in the journal Nature.

The results further demonstrate the highly polygenic nature of schizophrenia risk. The implicated genes represent a large range of biological functions and converge on a few well-known pathways, chiefly FMRP. The most significant individual finding remains the HLA region, adding to the now widely-held idea that immunity plays an important role in the etiology of schizophrenia.

What now? The mapping of functional alleles in individual genes is the logical next step, but will be a major challenge. Some critics will express skepticism that we have learned much more than we knew after the last large GWAS. Clearly the GWAS method works for schizophrenia – but will we now want to study even larger samples? Skeptics might reasonably ask what we will learn from the next 100 markers that we have not already learned from the first 100.

As a field, we should challenge ourselves to run at least one of these findings to ground, establishing the functional risk alleles and using this information to formulate bold new hypotheses about the causes and treatment of schizophrenia. Even one new effective medication that comes out of these findings will make the entire effort worthwhile.

View all comments by Francis McMahon

Related News: Bigger Schizophrenia GWAS Reports More Than 100 Hits

Comment by:  Bryan Roth, SRF Advisor
Submitted 22 July 2014
Posted 22 July 2014

This is indeed a "landmark paper" and one eagerly awaited by the field of psychiatry, and likely medicine in general.

One thing to emphasize (which was nicely stated in Tom Insel's blog) is that in no case was an actual gene identified. As these are all rather large loci which contain both open reading frames (ORFs) as well as non-coding regions (introns and probably other yet to be identified non-coding RNAs), the real work will be to identify the precise mutation(s) associated with the loci.

Additionally, it will be critically important to determine the directionality of the mutation(s) identified for each locus. Thus, before embarking on a drug discovery expedition, it is important to know if the particular mutations augment or inhibit the activity of the particular molecular entity imputed.

If we take DRD2 (D2-dopamine receptor) as an example, it is important to know if the mutations reside in the coding region and, if so, whether they alter expression, signaling, signaling bias, neuronal targeting, and so on. If the mutation(s) are in non-coding regions (introns, promoter regions, non-coding 3'-region), it will be important to understand how this might alter the expression/function of DRD2. For essentially all of the targets imputed to drive a drug discovery program forward, it is essential to know this information.

Thus, for the calcium channels implicated (CACNA1C, CACNB2, and CACNA1I, which encode voltage-gated calcium channel subunits), we need to know how (and if) the mutations ultimately identified affect channel function, as the design of drugs at these targets will depend upon whether we need to augment or inhibit activity.

Finally, as each of these risk alleles has only a minute effect on the overall risk for schizophrenia, it is unknown whether creating a drug which modulates the activity of a single target could ever lead to a population-wide effect on disease progression/outcome.

Nonetheless, these findings are foundational for the field and provide proof for the power of this approach.

View all comments by Bryan Roth

Related News: Bigger Schizophrenia GWAS Reports More Than 100 Hits

Comment by:  Philip Seeman (Disclosure)
Submitted 22 July 2014
Posted 22 July 2014

Of the many DNA regions found to be associated with schizophrenia in this study (Ripke et al., 2014), the only region that is associated with current treatment is the dopamine D2 receptor. The study shows that this DNA region is 50,000 bases away from the D2 gene and is in the DNA promoter region that controls the expression of the D2 gene. Let’s hope that other DNA regions may lead to improved treatment.

These current results support Van Rossum’s long-standing hyper-dopamine transmission theory of schizophrenia. While there are many causes for schizophrenia, it appears that a final common path for clinical signs and symptoms goes through dopamine D2 receptors.


Ripke S. et al. Nature, July 21, 2014. doi 10.1038.nature13595.

View all comments by Philip Seeman

Related News: Bigger Schizophrenia GWAS Reports More Than 100 Hits

Comment by:  Zoran Vukadinovic
Submitted 23 July 2014
Posted 31 July 2014

My brief comment will focus on one of the findings which is replicated in this study. Namely, this is the second GWAS which has reported that the gene encoding the CaV3.3 subtype of T-type calcium channel (CACNA1L/I) is involved in the pathophysiology of schizophrenia. The reference for the first study can be found below (Strange et al., 2012).

This is an important finding, as CaV3.3 is expressed in the thalamic reticular nucleus (TRN) and has a role in the generation of sleep spindles (Astori et al., 2011), which are markedly reduced in schizophrenia (Ferrarelli and Tononi, 2011). Thus, the finding reported in this GWAS has an important potential pathophysiologic correlate. Sleep spindle reductions in some individuals with schizophrenia may be related to abnormalities of the CaV3.3 subtype the of T-type calcium channel. How this could lead to other deficits in this illness remains to be determined (see Vukadinovic, 2011).

Epidemiologic evidence suggests that cannabis use may be the strongest environmental risk factor for the development of schizophrenia. It is interesting and potentially important that exogenous cannabinoids were found to directly, and independently of, cannabinoid receptors, block T-type calcium channels (including the CaV3.3 subtype) in both cell cultures and neuronal tissues (Ross et al., 2008). This effect may be related to the psychotogenic potential of exogenous cannabinoids (Vukadinovic et al., 2013).

Thus, the now replicated finding that the CACNA1L/I gene may be a susceptibility gene for the development of schizophrenia fits with pathophysiologic evidence of sleep spindle reductions (and possibly TRN deficits) and may, moreover, intersect with a major environmental risk factor (i.e., cannabis use). These three issues may help elucidate the etiology of schizophrenia in at least some patients and should be investigated further.


Strange A., Riley B.P., Spencer C.C.A., Morris D.W., Pirinen M., O’Dushlaine C.T., et al., 2012. Genome-wide association study implicates HLA-C*01:02 as a risk factor at the major histocompatibility complex locus in schizophrenia. Biol Psychiatry . 2012 Oct 15 ; 72(8):620-8. Abstract

Astori S, Wimmer RD, Prosser HM, Corti C, Corsi M, Liaudet N, Volterra A, Franken P, Adelman JP, Lüthi A. The Ca(V)3.3 calcium channel is the major sleep spindle pacemaker in thalamus. Proc Natl Acad Sci U S A . 2011 Aug 16 ; 108(33):13823-8. Abstract

Ferrarelli F, Tononi G. The thalamic reticular nucleus and schizophrenia. Schizophr Bull . 2011 Mar ; 37(2):306-15. Abstract

Vukadinovic Z. Sleep abnormalities in schizophrenia may suggest impaired trans-thalamic cortico-cortical communication: towards a dynamic model of the illness. Eur J Neurosci . 2011 Oct ; 34(7):1031-9. Abstract

Ross HR, Napier I, Connor M. Inhibition of recombinant human T-type calcium channels by Delta9-tetrahydrocannabinol and cannabidiol. J Biol Chem . 2008 Jun 6 ; 283(23):16124-34. Abstract

Vukadinovic Z, Herman MS, Rosenzweig I. Cannabis, psychosis and the thalamus: a theoretical review. Neurosci Biobehav Rev . 2013 May ; 37(4):658-67. Abstract

View all comments by Zoran Vukadinovic

Related News: Bigger Schizophrenia GWAS Reports More Than 100 Hits

Comment by:  Hugo Geerts
Submitted 4 August 2014
Posted 6 August 2014

While this might be a blockbuster breakthrough study from an academic point of view, I would caution that there is still a very long way to go before this could be turned into potential drug targets and discovery programs. Many of the SNPs are contributing very little to the schizophrenia phenotype, suggesting that there might be many different ways to arrive at the same phenotype.

One could say that, for schizophrenia, we are now at a situation in the Alzheimer’s field some 22 years ago when ApoE (major risk factor with an OR of about 4) in sporadic patients and APP in familial patients were identified. Yet no drug program focused on ApoE has entered a Phase 2 POC study, and the (many and expensive) APP clinical programs all have failed to live up to expectations in the clinic so far. It suggests that the one gene-one phenotype hypothesis likely is much too simple. Also, the SNPs listed do not include currently pursued clinical targets such as PDE10 or α7 nAChR.

Under the leadership of Dr. Zaven Khachaturian and the Alzheimer's Association, we have set up a workgroup on how to go from Big (-omics) Data to Smart Data; i.e., how could we generate actionable knowledge (in a drug discovery sense) from all the databases that identify "correlations" or "associations" with certain clinical phenotypes in Alzheimer’s disease? I was wondering if the time would be right to start a similar pre-competitive workgroup initiative in schizophrenia so as to incentivize the pharmaceutical industry by providing it with useful, actionable knowledge about what possible targets are worth pursuing for a large number of patients and how to best affect these targets (i.e., agonism or antagonism).

View all comments by Hugo Geerts

Related News: WCPG 2014—Genomics Smorgasbord: Varied Samplings for Schizophrenia

Comment by:  Anna Need
Submitted 17 October 2014
Posted 17 October 2014

Fantastic summary, Michele. Thanks! Was unable to go this year, so it's great to hear the highlights.

View all comments by Anna Need

Related News: Common Pathways Found for Some Psychiatric Disorders

Comment by:  Alexander B. Niculescu
Submitted 29 January 2015
Posted 29 January 2015

Biological pathway level analyses are a step forward in the field and are more reproducible compared to SNP level analyses, as we and others have shown. This paper describes nice, comprehensive pathway analyses, using different methods and looking at what is reproducible across methods (which is a strength) and across disorders (which is not a strength, as you get more non-specific things involved in basic brain dysfunction/housekeeping).

The limitations are: 1) the input set of SNPs from the original data, which are by no means definitive; and 2) the fact that the pathway programs used are by nature imperfect, evolving, and not designed specifically for neuropsychiatric disorders, but rather incorporating information that comes more from the cancer literature. More focused approaches such as Convergent Functional Genomics, which prioritize at a gene level the input list for specific involvement in neuropsychiatric disorders, may be more useful as a first step, and then pathway analyses done on top of those prioritized lists would be more disease specific. We have demonstrated the comparative reproducibility of these various approaches in a prior paper published in 2012 (Ayalew et al., 2012).


Ayalew M, Le-Niculescu H, Levey DF, Jain N, Changala B, Patel SD, Winiger E, Breier A, Shekhar A, Amdur R, Koller D, Nurnberger JI, Corvin A, Geyer M, Tsuang MT, Salomon D, Schork NJ, Fanous AH, O'Donovan MC, Niculescu AB. Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction. Mol Psychiatry. 2012 Sep; 17(9):887-905. Abstract

View all comments by Alexander B. Niculescu