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Optimum designs for next-generation sequencing to discover rare variants for common complex disease.

ABSTRACT: Recent advances in next-generation sequencing technologies make it affordable to search for rare and functional variants for common complex diseases systematically. We investigated strategies for enriching rare variants in the samples selected for sequencing so as to optimize the power for their discovery. In particular, we investigated the roles of alternative sources of enrichment in families through computer simulations. We showed that linkage information, extreme phenotype, and nonrandom ascertainment, such as multiply affected families, constitute different sources for enriching rare and functional variants in a sequencing study design. Linkage is well known to have limited power for detecting small genetic effects, and hence not considered to be a powerful tool for discovering variants for common complex diseases. However, those families with some degree of family-specific linkage evidence provide an effective sampling strategy to sub-select the most linkage-informative families for sequencing. Compared with selecting subjects with extreme phenotypes, linkage evidence performs better with larger families, while extreme-phenotype method is more efficient with smaller families. Families with multiple affected siblings were found to provide the largest enrichment of rare variants. Finally, we showed that combined strategies, such as selecting linkage-informative families from multiply affected families, provide much higher enrichment of rare functional variants than either strategy alone.

SUBMITTER: Shi G

PROVIDER: S-EPMC3596871 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Optimum designs for next-generation sequencing to discover rare variants for common complex disease.

Shi Gang G Rao D C DC

Genetic epidemiology 20110526 6

Recent advances in next-generation sequencing technologies make it affordable to search for rare and functional variants for common complex diseases systematically. We investigated strategies for enriching rare variants in the samples selected for sequencing so as to optimize the power for their discovery. In particular, we investigated the roles of alternative sources of enrichment in families through computer simulations. We showed that linkage information, extreme phenotype, and nonrandom asc ...[more]

PMID: 21618604

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Project description:The cost of next-generation sequencing is now approaching that of early GWAS panels, but is still out of reach for large epidemiologic studies and the millions of rare variants expected poses challenges for distinguishing causal from non-causal variants. We review two types of designs for sequencing studies: two-phase designs for targeted follow-up of genomewide association studies using unrelated individuals; and family-based designs exploiting co-segregation for prioritizing variants and genes. Two-phase designs subsample subjects for sequencing from a larger case-control study jointly on the basis of their disease and carrier status; the discovered variants are then tested for association in the parent study. The analysis combines the full sequence data from the substudy with the more limited SNP data from the main study. We discuss various methods for selecting this subset of variants and describe the expected yield of true positive associations in the context of an on-going study of second breast cancers following radiotherapy. While the sharing of variants within families means that family-based designs are less efficient for discovery than sequencing unrelated individuals, the ability to exploit co-segregation of variants with disease within families helps distinguish causal from non-causal ones. Furthermore, by enriching for family history, the yield of causal variants can be improved and use of identity-by-descent information improves imputation of genotypes for other family members. We compare the relative efficiency of these designs with those using unrelated individuals for discovering and prioritizing variants or genes for testing association in larger studies. While associations can be tested with single variants, power is low for rare ones. Recent generalizations of burden or kernel tests for gene-level associations to family-based data are appealing. These approaches are illustrated in the context of a family-based study of colorectal cancer.

Project description:BACKGROUND: Multiple genes have been implicated by association studies in altering inflammatory bowel disease (IBD) predisposition. Paediatric patients often manifest more extensive disease and a particularly severe disease course. It is likely that genetic predisposition plays a more substantial role in this group. OBJECTIVE: To identify the spectrum of rare and novel variation in known IBD susceptibility genes using exome sequencing analysis in eight individual cases of childhood onset severe disease. DESIGN: DNA samples from the eight patients underwent targeted exome capture and sequencing. Data were processed through an analytical pipeline to align sequence reads, conduct quality checks, and identify and annotate variants where patient sequence differed from the reference sequence. For each patient, the entire complement of rare variation within strongly associated candidate genes was catalogued. RESULTS: Across the panel of 169 known IBD susceptibility genes, approximately 300 variants in 104 genes were found. Excluding splicing and HLA-class variants, 58 variants across 39 of these genes were classified as rare, with an alternative allele frequency of <5%, of which 17 were novel. Only two patients with early onset Crohn's disease exhibited rare deleterious variations within NOD2: the previously described R702W variant was the sole NOD2 variant in one patient, while the second patient also carried the L1007 frameshift insertion. Both patients harboured other potentially damaging mutations in the GSDMB, ERAP2 and SEC16A genes. The two patients severely affected with ulcerative colitis exhibited a distinct profile: both carried potentially detrimental variation in the BACH2 and IL10 genes not seen in other patients. CONCLUSION: For each of the eight individuals studied, all non-synonymous, truncating and frameshift mutations across all known IBD genes were identified. A unique profile of rare and potentially damaging variants was evident for each patient with this complex disease.

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Optimum designs for next-generation sequencing to discover rare variants for common complex disease.

Publications

Optimum designs for next-generation sequencing to discover rare variants for common complex disease.

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