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Chromosomal Mishaps in Autism Harbor Schizophrenia Candidate Genes

22 May 2012. Abnormal rearrangements of chromosome pieces can provide some useful genetic leads in neurodevelopmental disorders, according to a study published 27 April in Cell. Led by James Gusella of Harvard Medical School, Boston, Massachusetts, the study sequenced regions of balanced chromosomal abnormalities (BCAs) that had been found in people with neurodevelopmental disorders, including autism, to precisely pinpoint the genes disrupted. This turned up 33 genes, 22 of which were new to these disorders, and seven of which have links to schizophrenia. The findings reinforce hypotheses that autism and schizophrenia have genetic links (see SRF related news story), and suggest that how a gene is disrupted may influence which disorder develops.

BCAs result when chromosomes break and reattach in the wrong position during cell division, and include inversions (a broken piece reattaches in the wrong orientation), insertions (a broken piece embeds itself into the wrong chromosome), and translocations (different chromosomes exchange broken bits). BCAs are typically detected microscopically with a karyotype (see SRF related news story), but to get at which genes, if any, are disrupted by these rearrangements requires higher resolution of the regions of breakage and reattachment, called breakpoints. For example, the breakpoints of a translocation between chromosomes 1 and 11 in a Scottish family beset by schizophrenia and other psychiatric disorders led researchers to DISC1 (see SRF related news story). However, the microarrays that currently dominate the search for structural variation miss BCAs.

The new study gets down to nucleotide resolution by targeting and sequencing the BCA breakpoints, which in most cases pointed to a single gene or regulatory region. This locus precision complements other strategies for finding disease-related variation, such as the more common copy number variation (CNV)—the deletion or duplication of multigene-sized chunks of DNA—and exome sequencing, which examines only protein coding regions.

Broken genes
First author Michael Talkowski and colleagues began with 38 individuals already flagged as BCA carriers by karyotyping. Half of the subjects were diagnosed with autism, and the other half with a neurodevelopmental disorder, which for some included features of autism. The researchers applied a series of techniques to locate the BCAs. This included the use of “jumping libraries,” in which the researchers cut each genome into relatively long fragments (up to 4.5 kb), then sequenced short stretches at the ends. The fragments could then be used as a kind of molecular tape measure: if the end sequences match to places in a reference sequence that are closer together or farther apart than the fragment length, then that fragment must contain extra DNA or missing DNA, respectively (Talkowski et al., 2011).

Sequencing then divulged the genes disrupted by the BCAs—if a gene was not specifically hit, the researchers looked for expression changes in genes near the breakpoint in banked lymphoblast cells for most of the subjects, which could indicate disturbance of a regulatory region. This strategy highlighted 33 loci, including genes already associated with autism (e.g., AUTS2, FOXP1, and CDKL5), genes responsible for the phenotype in known microdeletion syndromes (e.g., MBD5), completely novel genes (e.g., KIRREL3, ZNF507, CHD8), and several genes associated with schizophrenia, including TCF4, ZNF804A, GRIN2B, ANK3, PDE10A, and EHMT1.

Though BCAs occur at a sixfold higher frequency in autism than in controls, and 36 out of 38 BCAs identified in this study were de novo, the researchers sought extra evidence for the involvement of these genes in the disorder. Given the rarity of BCAs, they turned to CNVs, analyzing data from 19,556 cases with a variety of neurodevelopmental disorders (including 25 percent with autism) and 13,991 controls. This revealed that cases with neurodevelopmental disorders carried CNVs that included the 33 loci flagged by BCAs more often than controls did (p = 2.07 x 10-47, OR = 5.12). Based on analyses of individual genes, the researchers offered some evidence that for 21 of these genes, CNVs were overrepresented in cases versus controls (either p <0.10, or when numbers were too low for adequate statistical power, at least three CNVs in cases and none in controls); this group included all the genes mentioned above, except for ANK3. Analyzed by category, there was a collective increase in CNV burden for the genes already associated with autism (p = 7.74 x 10-20, OR = 3.6), the genes contributing to microdeletion syndrome phenotypes (p = 1.64 x 10-26, OR = 10.2), the 22 genes new to autism and neurodevelopmental disorders (p = 2.21 x 10-15, OR = 4.1), and the genes associated with psychiatric disorders including schizophrenia (p = 5.1 x 10-15, OR = 6.7).

In the commons
Linking autism to genes in this last category raises the question of how the same genes confer risk for different disorders. These genes have been associated with schizophrenia through genomewide association studies (GWAS) and candidate gene studies of common variants, which suggests that how a gene is disrupted may matter. For example, common variants that subtly alter gene function might increase risk for one disorder, whereas wholesale inactivation of the same gene by BCAs or CNVs might result in a different disorder.

To explore the contributions of common variation in these BCA-identified genes, the researchers turned to GWAS datasets for schizophrenia and autism. In the largest-to-date schizophrenia GWAS dataset (see SRF related news story), they found that people with schizophrenia had an enrichment of GWAS-determined risk alleles in the BCA-identified genes compared to other parts of the genome (p = 0.0009). A similar enrichment was not found in GWAS datasets for Crohn’s disease and other traits. On the other hand, they also found an enrichment of risk alleles in these genes in the datasets for two autism GWAS (Wang et al., 2009; Weiss et al., 2009). Though this does not jibe with the notion that a simple distinction between common and rare variants dictates which disorder develops, it does show that a palette of variation in these genes contributes to diverse brain disorders, and argues that functional annotation of these genes and their variants is paramount.

That many genes in this study had already been associated with other disorders gives a vote of confidence to pursuing these oddball BCAs, and suggests that the new genes will also be relevant: indeed, last month one of these, CHD8, was fingered in a sequencing study of the autism exome (see SRF related news story). The overlap between schizophrenia and autism genes also supports the notion that even adult-onset psychiatric diseases stem from aberrant neurodevelopment, and suggests that chasing down the biology of these genes will point to key processes in brain development.—Michele Solis.

Reference:
Talkowski ME, Rosenfeld JA, Blumenthal I, Pillalamarri V, Chiang C, Heilbut A, Ernst C, Hanscom C, Rossin E, Lindgren AM, Pereira S, Ruderfer D, Kirby A, Ripke S, Harris DJ, Lee JH, Ha K, Kim HG, Solomon BD, Gropman AL, Lucente D, Sims K, Ohsumi TK, Borowsky ML, Loranger S, Quade B, Lage K, Miles J, Wu BL, Shen Y, Neale B, Shaffer LG, Daly MJ, Morton CC, Gusella JF. Sequencing Chromosomal Abnormalities Reveals Neurodevelopmental Loci that Confer Risk across Diagnostic Boundaries. Cell. 2012 Apr 27;149(3):525-37. Abstract

 
Comments on News and Primary Papers
Comment by:  Ben Pickard
Submitted 23 May 2012 Posted 24 May 2012

The paper by Talkowski and colleagues describes the...  Read more


View all comments by Ben Pickard

Comment by:  Patrick Sullivan, SRF AdvisorJin Szatkiewicz
Submitted 29 May 2012 Posted 29 May 2012
  I recommend the Primary Papers

In this exceptional paper, the authors combined new...  Read more


View all comments by Patrick Sullivan
View all comments by Jin Szatkiewicz

Comment by:  Bernard Crespi
Submitted 29 May 2012 Posted 29 May 2012
  I recommend the Primary Papers

Balanced chromosomal abnormalities (BCAs) provide...  Read more


View all comments by Bernard Crespi
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