Increased exonic de novo mutation rate in individuals with schizophrenia

Abstract

Genome Biology 2011, 12(Suppl 1):I18 Deep exome resequencing is a powerful approach for delineating patterns of protein-coding variation among genes, pathways, individuals and populations. We analyzed exome data from 2,440 individuals of European and African ancestry as part of the National Heart, Lung, and Blood Institute's Exome Project, the aim of which is to discover novel genes and mechanisms that contribute to heart, lung and blood disorders. Each exome was sequenced to a mean coverage of 116×, allowing detailed inferences about the population genomic patterns of both common variation and rare coding variation. We identifi ed more than 500,000 single nucleotide variations, the majority of which were novel and rare (76% of variants had a minor allele frequency of less than 0.1%), refl ecting the recent dramatic increase in the size of the human population. The unprecedented magnitude of this dataset allowed us to rigorously characterize the large variation in nucleotide diversity among genes (ranging from 0 to 1.32%), as well as the role of positive and purifying selection in shaping patterns of protein-coding variation and the diff erential signatures of population structure from rare and common variation. This dataset provides a framework for personal genomics and is an important resource that will allow inferences of broad importance to human evolution and health. I2 Abstract not submitted for online publication. I3 Are clinical genomes already becoming semi-routine for patient care?

10 Years of GWAS Discovery: Biology, Function, and Translation

“…26 However, genetic architecture, described as the mix of rare and common variants, is likely to differ between psychiatric disorders, as is already being observed for the higher rates of rare, de novo penetrant CNVs and single-nucleotide variants found in autism than in schizophrenia or bipolar disorder. [121][122][123][124][125][126][127][128][129] PRS studies are being utilized extensively to investigate disease heterogeneity and contributions from environmental risk factors.…”

Disease gene identification strategies for exome sequencing

“…These remarkable findings in intellectual disability have recently been replicated in sporadic forms of autism 39 and schizophrenia, 5 indicating that de novo mutations may explain a considerable proportion of the sporadic forms of common neurodevelopmental disorders. 4,40 Note that, as for the other strategies, variants prioritized in this way are more likely to be causative for disease, but de novo occurrence in itself is not sufficient evidence, and follow-up studies are required to identify recurrence or functional proof of pathogenicity. In addition, the focus on variants that are present only in an affected child and not in the parents does not only enrich for de novo mutations but also for sequencing and mapping artifacts, and therefore requires high sequencing accuracy and equal coverage in all three samples investigated.…”

Genetic studies of schizophrenia: an update

“…Rare variants (including CNVs and DNMs) may be pathologically causal. Unfortunately, due to the extremely low frequencies of these rare variants, only a few are reported in cases [36,[78][79][80] . For example, the largest exome sequencing project reported a signifi cantly higher rate of rare (frequency <0.1%), disruptive mutations in cases compared to controls among gene sets that had previously been associated with SCZ [80] .…”

“…This hypothesis did not receive much attention in genetic studies until recently, when high-throughput DNA sequencing of SCZ families provided direct evidence that affected offspring have excess DNMs across the genome [72,73] . Further studies of DNMs in individual genes [74,75] , a particular set of genes [76,77] , or the exome [78][79][80] , also provided evidence that DNMs are enriched in SCZ patients. Direct measurement also indicates that SCZ patients have a higher mutation rate [76] .…”