Exome sequencing and the genetic basis of complex traits

Abstract

Exome sequencing is emerging as a popular approach to study the effect of rare coding variants on complex phenotypes. The promise of exome sequencing is grounded in theoretical population genetics and in empirical successes of candidate gene sequencing studies. Many projects aimed at common diseases are underway, and their results are eagerly anticipated. In this Perspective, using exome sequencing data from 438 individuals, we discuss several aspects of exome sequencing studies that we view as particularly important. We review processing and quality control of raw sequence data, evaluate the statistical properties of exome sequencing studies, discuss rare variant burden tests to detect association to phenotypes, and demonstrate the importance of accounting for population stratification in the analysis of rare variants. We conclude that enthusiasm for exome sequencing studies of complex traits should be combined with the caution that thousands of samples may be required to reach sufficient statistical power.

Phenotypic extremes in rare variant study designs

“…The search for rare variants that influence phenotypic variation has been made possible through the development of nextgeneration sequencing technologies. 1,2 Rare variant association studies (RVASs) are a more complex process compared with CVASs, as they include both discovery of variation contributing to disease and subsequent testing of the discovered variation. 3,4 Statistical analysis of rare variation is further complicated by the limited number of alleles of a given variant in the sample that necessitates the aggregation of variants across a gene or region.…”

“…Furthermore, extreme sampling strategies in the population cohorts have also shown association between rare variation in these genes and low HDL-C. 23 Here, we demonstrate empirically different strength of association between rare variants in ABCA1 with HDL-C using a random population-based sample in contrast to a phenotypic extremeselected sample. Based on this observation we performed a simulation study to attempt to reconcile the causes of the differences in association and answer the following questions: (1) What is the impact of phenotypic selection on rare variant study designs in contrast to common variant association? ; and (2) What impact does this have when meta-analyzing rare variant results?…”

No evidence for rare recessive and compound heterozygous disruptive variants in schizophrenia

“…Recently, large-scale exome-sequencing studies have searched for rare variants that strongly increase risk, 8,9 although the relatively high baseline rate of rare neutral coding variation makes this challenging. 10 To focus on rare variants that are a priori more likely to be highly penetrant for disease, one approach is to study de novo mutations, as these are effectively uncensored by selection pressures.…”

A regulatory mutant on TRIM26 conferring the risk of nasopharyngeal carcinoma by inducing low immune response

“…Recently, the identification of genes responsible for diseases has been facilitated with newly developed technologies, particularly the targeted capturing the genome of interest, followed by sequencing. Exome sequencing, emerging as a popular approach, has been widely applied to assess the associations of coding variations, both common and rare, with complex phenotypes 15, 40, 41. The present study first applied a targeted MHC sequencing to human cancer research followed by a two‐stage population‐based replication study, successfully identifying 5 SNPs with consistent associations and eventually pointing to a novel SNP rs117565607 at TRIM26 , with the strongest association (OR = 1.9090, P combined  = 2.750 × 10 −19 ) and potential function.…”

“…Target‐enrichment strategy is the method, in which genomic regions of particular interest are selectively captured before sequencing 14, 15. This approach has proved to be a cost‐effective solution for studying MHC region,16 particularly facilitating the population‐based research.…”