Dataset Information

Simulation of Finnish population history, guided by empirical genetic data, to assess power of rare-variant tests in Finland.

ABSTRACT: Finnish samples have been extensively utilized in studying single-gene disorders, where the founder effect has clearly aided in discovery, and more recently in genome-wide association studies of complex traits, where the founder effect has had less obvious impacts. As the field starts to explore rare variants' contribution to polygenic traits, it is of great importance to characterize and confirm the Finnish founder effect in sequencing data and to assess its implications for rare-variant association studies. Here, we employ forward simulation, guided by empirical deep resequencing data, to model the genetic architecture of quantitative polygenic traits in both the general European and the Finnish populations simultaneously. We demonstrate that power of rare-variant association tests is higher in the Finnish population, especially when variants' phenotypic effects are tightly coupled with fitness effects and therefore reflect a greater contribution of rarer variants. SKAT-O, variable-threshold tests, and single-variant tests are more powerful than other rare-variant methods in the Finnish population across a range of genetic models. We also compare the relative power and efficiency of exome array genotyping to those of high-coverage exome sequencing. At a fixed cost, less expensive genotyping strategies have far greater power than sequencing; in a fixed number of samples, however, genotyping arrays miss a substantial portion of genetic signals detected in sequencing, even in the Finnish founder population. As genetic studies probe sequence variation at greater depth in more diverse populations, our simulation approach provides a framework for evaluating various study designs for gene discovery.

SUBMITTER: Wang SR

PROVIDER: S-EPMC4067550 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Simulation of Finnish population history, guided by empirical genetic data, to assess power of rare-variant tests in Finland.

Wang Sophie R SR Agarwala Vineeta V Flannick Jason J Chiang Charleston W K CW Altshuler David D Hirschhorn Joel N JN

American journal of human genetics 20140424 5

Finnish samples have been extensively utilized in studying single-gene disorders, where the founder effect has clearly aided in discovery, and more recently in genome-wide association studies of complex traits, where the founder effect has had less obvious impacts. As the field starts to explore rare variants' contribution to polygenic traits, it is of great importance to characterize and confirm the Finnish founder effect in sequencing data and to assess its implications for rare-variant associ ...[more]

PMID: 24768551

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Project description:BackgroundBoth common and rare genetic variants have been shown to contribute to the etiology of complex diseases. Recent genome-wide association studies (GWAS) have successfully investigated how common variants contribute to the genetic factors associated with common human diseases. However, understanding the impact of rare variants, which are abundant in the human population (one in every 17 bases), remains challenging. A number of statistical tests have been developed to analyze collapsed rare variants identified by association tests. Here, we propose a haplotype-based approach. This work inspired by an existing statistical framework of the pedigree disequilibrium test (PDT), which uses genetic data to assess the effects of variants in general pedigrees. We aim to compare the performance between the haplotype-based approach and the rare variant-based approach for detecting rare causal variants in pedigrees.ResultsExtensive simulations in the sequencing setting were carried out to evaluate and compare the haplotype-based approach with the rare variant methods that drew on a more conventional collapsing strategy. As assessed through a variety of scenarios, the haplotype-based pedigree tests had enhanced statistical power compared with the rare variants based pedigree tests when the disease of interest was mainly caused by rare haplotypes (with multiple rare alleles), and vice versa when disease was caused by rare variants acting independently. For most of other situations when disease was caused both by haplotypes with multiple rare alleles and by rare variants with similar effects, these two approaches provided similar power in testing for association.ConclusionsThe haplotype-based approach was designed to assess the role of rare and potentially causal haplotypes. The proposed rare variants-based pedigree tests were designed to assess the role of rare and potentially causal variants. This study clearly documented the situations under which either method performs better than the other. All tests have been implemented in a software, which was submitted to the Comprehensive R Archive Network (CRAN) for general use as a computer program named rvHPDT.

Dataset Information

Simulation of Finnish population history, guided by empirical genetic data, to assess power of rare-variant tests in Finland.

Publications

Simulation of Finnish population history, guided by empirical genetic data, to assess power of rare-variant tests in Finland.

Similar Datasets

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