detecting low frequent loss-of-function alleles in genome wide association studies with red hair color as example检测低频繁功能丧失的等位基因的全基因组研究协会红头发的颜色为例.pdfVIP

Detecting Low Frequent Loss-of-Function Alleles in Genome Wide Association Studies with Red Hair Color as Example 1 2 1 2 ´ 2,3 Fan Liu *, Maksim V. Struchalin , Kate van Duijn , Albert Hofman , Andre G. Uitterlinden , Cornelia 2 2 1 van Duijn , Yurii S. Aulchenko , Manfred Kayser 1 Department of Forensic Molecular Biology, Erasmus University Medical Center, Rotterdam, The Netherlands, 2 Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands, 3 Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands Abstract Multiple loss-of-function (LOF) alleles at the same gene may influence a phenotype not only in the homozygote state when alleles are considered individually, but also in the compound heterozygote (CH) state. Such LOF alleles typically have low frequencies and moderate to large effects. Detecting such variants is of interest to the genetics community, and relevant statistical methods for detecting and quantifying their effects are sorely needed. We present a collapsed double heterozygosity (CDH) test to detect the presence of multiple LOF alleles at a gene. When causal SNPs are available, which may be the case in next generation genome sequencing studies, this CDH test has overwhelmingly higher power than single SNP analysis. When causal SNPs are not directly available such as in current GWA settings, we show the CDH test has higher power than standard single SNP analysis if tagging SNPs are in linkage disequilibrium with the underlying causal SNPs to at least a moderate degree (r2.0.1). The test is implemente