Detecting Low Frequent Loss-of-Function Alleles in Genome Wide Association Studies with Red Hair Color as Example

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 implemented for genome-wide analysis in the publically available software package GenABEL which is based on a sliding window approach. We provide the proof of principle by conducting a genome-wide CDH analysis of red hair color, a trait known to be influenced by multiple loss-of-function alleles, in a total of 7,732 Dutch individuals with hair color ascertained. The association signals at the MC1R gene locus from CDH were uniformly more significant than traditional GWA analyses (the most significant P for CDH = 3.11×10−142 vs. P for rs258322 = 1.33×10−66). The CDH test will contribute towards finding rare LOF variants in GWAS and sequencing studies.

Dissecting Genome-Wide Association Signals for Loss-of-Function Phenotypes in Sorghum Flavonoid Pigmentation Traits

“…Loss-of-function variants are a common source of natural variation, and recently methods have been developed to identify multiple, low-frequency loss-of-function alleles at the same gene in GWAS (Liu et al 2011). The loss-of-function genome scan approach we used here allowed us to precisely map a high frequency loss-of-function allele to the exclusion of nearby indirect associations.…”

A Genome-Wide Association Study Identifies the Skin Color Genes IRF4, MC1R, ASIP, and BNC2 Influencing Facial Pigmented Spots

“…There are six SNPs within MC1R which are frequent in Europeans (MAF>1%) and associate with skin color together in a compound heterozygous manner (Liu et al, 2011). Compound heterozygosity implies that if both homologous chromosomes carry 1 effect allele but in different SNPs, the effect is similar to that of a homozygous allele.…”

Colorful DNA polymorphisms in humans

“…In more common situations LOF variants may have smaller effects and lower frequencies, and so be undetectable. Recently, a method has been proposed to detect CH-like associations in GWAS, which demonstrated an increased statistical power using the relationship between MC1R variants and red hair as an example [116]. While the LOF alleles in MC1R are important, they themselves alone cannot explain all red hair cases since some dizygotic twins carrying identical MC1R haplotypes were found to have discordant hair colors [117].…”