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- Guey, Lin T., et al.
(författare)
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Power in the Phenotypic Extremes: A Simulation Study of Power in Discovery and Replication of Rare Variants
- 2011
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Ingår i: Genetic Epidemiology. - : Wiley. - 0741-0395. ; 35:4, s. 236-246
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Tidskriftsartikel (refereegranskat)abstract
- Next-generation sequencing technologies are making it possible to study the role of rare variants in human disease. Many studies balance statistical power with cost-effectiveness by (a) sampling from phenotypic extremes and (b) utilizing a two-stage design. Two-stage designs include a broad-based discovery phase and selection of a subset of potential causal genes/variants to be further examined in independent samples. We evaluate three parameters: first, the gain in statistical power due to extreme sampling to discover causal variants; second, the informativeness of initial (Phase I) association statistics to select genes/variants for follow-up; third, the impact of extreme and random sampling in (Phase 2) replication. We present a quantitative method to select individuals from the phenotypic extremes of a binary trait, and simulate disease association studies under a variety of sample sizes and sampling schemes. First, we find that while studies sampling from extremes have excellent power to discover rare variants, they have limited power to associate them to phenotype-suggesting high false-negative rates for upcoming studies. Second, consistent with previous studies, we find that the effect sizes estimated in these studies are expected to be systematically larger compared with the overall population effect size; in a well-cited lipids study, we estimate the reported effect to be twofold larger. Third, replication studies require large samples from the general population to have sufficient power; extreme sampling could reduce the required sample size as much as fourfold. Our observations offer practical guidance for the design and interpretation of studies that utilize extreme sampling. Genet. Epidemiol. 35: 236-246, 2011. (c) 2011 Wiley-Liss, Inc.
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| 2. |
- Shea, Jessica, et al.
(författare)
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Comparing strategies to fine-map the association of common SNPs at chromosome 9p21 with type 2 diabetes and myocardial infarction
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:8, s. 114-801
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Tidskriftsartikel (refereegranskat)abstract
- Noncoding variants at human chromosome 9p21 near CDKN2A and CDKN2B are associated with type 2 diabetes(1-4), myocardial infarction(5-7), aneurysm(8), vertical cup disc ratio(9) and at least five cancers(10-16). Here we compare approaches to more comprehensively assess genetic variation in the region. We carried out targeted sequencing at high coverage in 47 individuals and compared the results to pilot data from the 1000 Genomes Project. We imputed variants into type 2 diabetes and myocardial infarction cohorts directly from targeted sequencing, from a genotyped reference panel derived from sequencing and from 1000 Genomes Project low-coverage data. Polymorphisms with frequency >5% were captured well by all strategies. Imputation of intermediate-frequency polymorphisms required a higher density of tag SNPs in disease samples than is available on first-generation genome-wide association study (GWAS) arrays. Our association analyses identified more comprehensive sets of variants showing equivalent statistical association with type 2 diabetes or myocardial infarction, but did not identify stronger associations than the original GWAS signals.
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