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Neurexin-Neuroligin Regulate Synapse Form and Function

13 August 2012. Two new studies describe how neurexin, a molecule implicated in schizophrenia by genetic association, interacts with other molecules to assemble synapses during development and fine-tunes their signals in maturity. Together, the studies suggest that defects in neurexin or its binding partners can alter how signals are routed through the brain.

The first study, published August 5 in Nature Neuroscience, reports that neurexin cooperates with Syd-1 to organize the proteins on both sides of the synapse during development. Led by Stephan Sigrist of Freie Universität Berlin, Germany, the study reports that neurexin is destabilized in Drosophila lacking Syd-1, leading to postsynaptic abnormalities. The second study, published online August 2 in Science, reports a role for neurexin and its binding partner, neuroligin, in synaptic signaling after development is complete. Led by Joshua Kaplan at Harvard Medical School, Boston, the study reported that neurexin-neuroligin binding sharpened the timing of neurotransmitter release in the worm Caenorhabditis elegans.

Deletions of neurexin found in schizophrenia, autism, and other psychiatric disorders (see SRF related news story; SRF Live Discussion), along with mutations in neuroligin found in autism (e.g., Zhang et al., 2009), have intensified research into the basic science of these adhesion molecules. Neurexin typically pokes out of the tip of an emerging axon, and binds to neuroligin, a molecule located on the surface of the contacted neuron. Researchers are now delving into how this neurexin-neuroligin partnership governs the assembly of both sides of the synapse, including the localization of neurotransmitter-containing vesicles on the presynaptic side, and the clustering of receptors to receive these chemical messages on the postsynaptic side. The new studies find this partnership is crucial for coupling these two sides effectively.

A trans-synaptic assembler
In the Nature Neuroscience study, first authors David Owald, Omid Khorramshahi, and Varun Gupta studied synapse assembly in vivo at the Drosophila neuromuscular junction. This venue has advantages over mammalian systems because the latter seem to have compensatory processes that make it tricky to discern neurexin’s role in synapse assembly (Varoqueaux et al., 2006). But in Drosophila, removing neurexin (Nrx-1) or neuroligin (Nlg-1) leads to severe deficits (Li et al., 2007). Because previous work had found that Syd-1, a cytoplasmic scaffolding protein, promoted presynaptic assembly, the researchers tested whether it works in concert with neurexin and neuroligin. It seems to—synaptic bouton numbers (a measure of synapse formation) were similarly decreased in Syd-1, Nrx-1, and Nlg-1 single mutants compared to controls, and the numbers were not further reduced in double mutants (Syd-1 with Nrx-1, or Syd-1 with Nlg-1), suggesting these proteins work along the same pathway.

The researchers next found that Syd-1 helped to cluster Nrx-1 and Nlg-1. In Syd-1 mutants, fluorescently labeled Nrx-1 intensity was 30 percent of that found in controls, which was taken as a sign of fragmented Nrx-1 clusters. Likewise, Nlg-1 clustering decreased in Syd-1 mutants. Nlg-1 clusters were recovered, however, when Nrx-1 was overexpressed in Syd-1 mutants. This and other experiments led to a picture of trans-synaptic cooperation: Syd-1 binds to the cytoplasmic end of Nrx-1, recruits it to the active zone of a developing synapse, and stabilizes it enough to form clusters; these Nrx-1 clusters then promote clustering of Nlg-1 across the synapse.

But it’s not all about the presynaptic side telling the postsynaptic side what to do. Sigrist's group found that Nlg-1 clustering in turn stabilized existing presynaptic clusters of Syd-1 and a related protein called Liprin-α, which would otherwise disintegrate. On its own postsynaptic turf, Nlg-1 clustering also guided the proper formation of glutamate receptors: without Nlg-1 clusters, GluR2B subunits were incorporated into glutamate receptors before GluR2A subunits—a reversal of what normally happens.

In maturity
The report in Science adds an interesting twist by finding that neurexin signaling can influence even mature synapses. First author Zhitao Hu and colleagues studied the Nrx-1−Nlg-1 partnership in C. elegans, in which the usual location of these molecules is reversed, with Nrx-1 on the postsynaptic side and Nlg-1 on the presynaptic side. Using electrophysiology, the researchers asked whether the neurexin-neuroligin interaction mediated a previously reported suppression of neurotransmitter release observed upon inactivating a muscle microRNA (miR-1). When they combined the miR-1 mutation with the Nrx-1 or Nlg-1 mutation, this eliminated the release defect, suggesting that the miR-1 mutation in muscle needs working versions of Nrx-1 and Nlg-1 to carry out its effects on the presynaptic terminal.

To follow up on this clue, the researchers looked for changes in single Nrx-1 and Nlg-1 mutants. Though they did not turn up evidence for alterations in synapse formation or morphology that might reflect aberrant development, they did find that Nrx-1 or Nlg-1 inactivation increased quantal content, the number of synaptic vesicles released in response to an action potential, relative to controls. Looking at Nlg-1 mutants more carefully, they found that the ensuing currents recorded on the postsynaptic side were larger and decayed more slowly than controls, consistent with a slower and more prolonged release of synaptic vesicles. To see if this effect might also be at work in mammalian synapses, the researchers reanalyzed published data from synapses recorded in mouse triple knockouts lacking neuroligin-1, -2, and -3 (Varoqueaux et al., 2006). There, they uncovered a similar slowing of synaptic responses that stemmed from presynaptic changes.

Further experiments suggested that Nlg-1 normally sharpens these synaptic responses by inhibiting exocytosis of those synaptic vesicles far from the calcium channels—the stragglers that are released only when enough calcium drifts their way. The researchers found that a redistribution of presynaptic proteins involved in exocytosis could underlie this change. This further emphasizes that the precise location of synaptic proteins could matter very much for how synapses ultimately work, with even subtle changes in position leading to garbled consequences for synaptic communication.—Michele Solis.

Owald D, Khorramshahi O, Gupta VK, Banovic D, Depner H, Fouquet W, Wichmann C, Mertel S, Eimer S, Reynolds E, Holt M, Aberle H, Sigrist SJ. Cooperation of Syd-1 with Neurexin synchronizes pre- with postsynaptic assembly. Nat Neurosci. 2012 Aug 5. Abstract

Hu Z, Hom S, Kudze T, Tong XJ, Choi S, Aramuni G, Zhang W, Kaplan JM. Neurexin and Neuroligin Mediate Retrograde Synaptic Inhibition in C. elegans. Science. 2012 Aug 2. Abstract

Comments on News and Primary Papers
Comment by:  Christian Schaaf
Submitted 14 August 2012
Posted 14 August 2012

Neurexins and neuroligins are some of the best-characterized cell-adhesion molecules. They are trans-synaptic cell-adhesion molecules that mediate essential signaling between pre- and postsynaptic specializations, signaling that performs a central role in the brain’s ability to process information, and that is a key target in the pathogenesis of cognitive diseases (Südhof, 2008). And indeed, all human neurexin genes (NRXN1, NRXN2, NRXN3) and all (NLGN1, NGLN3, NLGN4X, NLGN4Y) but one human neuroligin gene (NLGN2) have been associated with autism. In addition, NRXN1 has also been associated with schizophrenia with high confidence (Kirov et al., 2009). Recent studies about neurexins and neuroligins are now making some inroads in two directions: 1) genotype-phenotype correlations, and 2) the basic science of how neurexins and neuroligins participate in the assembly of pre- and postsynaptic membranes, and how they mediate signaling between the two.

1. Schaaf et al. (Schaaf et al., 2012) reported on a cohort of 24 individuals with small NRXN1 deletions, and found that more C-terminal deletions, especially the ones encompassing the sequence encoding neurexin-1β, seem to predispose to both macrocephaly and epilepsy when compared to those only deleting N-terminal segments of the NRXN1 gene. Subsequently, Tanaka et al. (Tanaka et al., 2012) investigated the higher-order architecture of cell adhesion mediated by neurexin-1 and neuroligin-1, and found that the ectodomain complex of neurexin-1β and neuroligin-1 spontaneously assembles into crystals of a lateral, sheet-like superstructure topologically compatible with transcellular adhesion. However, this higher-order architecture was not formed between neuroligin-1 and the much longer neurexin-1α isoform, thereby suggesting a functional discrimination mechanism between synaptic contacts made by different isoforms of neurexin variants.

2. New studies that came out just last week provide intriguing insight into the underlying molecular mechanisms (Hu et al., 2012; Owald et al., 2012). Hu et al. show in C. elegans how neurexin and neuroligin mediate retrograde synaptic inhibition, with slow and prolonged postsynaptic responses in mutants of Nlg-1 or Nrx-1. In children with ASDs, it has been shown that acoustic responses are slower, and multisensory responses are integrated over a longer time window. In individuals with schizophrenia, abnormal sensory gating is a well-established phenomenon. The results of Hu’s study suggest that altered kinetics of synaptic responses could be an important cellular defect in ASDs and schizophrenia.


Südhof TC. Neuroligins and neurexins link synaptic function to cognitive disease. Nature . 2008 Oct 16 ; 455(7215):903-11. Abstract

Schaaf CP, Boone PM, Sampath S, Williams C, Bader PI, Mueller JM, Shchelochkov OA, Brown CW, Crawford HP, Phalen JA, Tartaglia NR, Evans P, Campbell WM, Chun-Hui Tsai A, Parsley L, Grayson SW, Scheuerle A, Luzzi CD, Thomas SK, Eng PA, Kang SH, Patel A, Stankiewicz P, Cheung SW. Phenotypic spectrum and genotype-phenotype correlations of NRXN1 exon deletions. Eur J Hum Genet . 2012 May 23. Abstract

Kirov G, Rujescu D, Ingason A, Collier DA, O'Donovan MC, Owen MJ. Neurexin 1 (NRXN1) deletions in schizophrenia. Schizophr Bull . 2009 Sep 1 ; 35(5):851-4. Abstract

Tanaka H, Miyazaki N, Matoba K, Nogi T, Iwasaki K, Takagi J. Higher-order architecture of cell adhesion mediated by polymorphic synaptic adhesion molecules neurexin and neuroligin. Cell Rep . 2012 Jul 26 ; 2(1):101-10. Abstract

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Comments on Related News

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.

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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

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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.

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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