CollapsABEL: An R library for detecting compound heterozygote alleles in genome-wide association studies

Background: Compound Heterozygosity (CH) in classical genetics is the presence of two different recessive mutations at a particular gene locus. A relaxed form of CH alleles may account for an essential proportion of the missing heritability, i.e. heritability of phenotypes so far not accounted for by single genetic variants. Methods to detect CH-like effects in genome-wide association studies (GWAS) may facilitate explaining the missing heritability, but to our knowledge no viable software tools for this purpose are currently available. Results: In this work we present the Generalized Compound Double Heterozygosity (GCDH) test and its implementation in the R package CollapsABEL. Time-consuming procedures are optimized for computational efficiency using Java or C++. Intermediate results are stored either in an SQL database or in a so-called big.matrix file to achieve reasonable memory footprint. Our large scale simulation studies show that GCDH is capable of discovering genetic associations due to CH-like interactions with much higher power than a conventional single-SNP approach under various settings, whether the causal genetic variations are available or not. CollapsABEL provides a user-friendly pipeline for genotype collapsing, statistical testing, power estimation, type I error control and graphics generation in the R language. Conclusions: CollapsABEL provides a computationally efficient solution for screening general forms of CH alleles in densely imputed microarray or whole genome sequencing datasets. The GCDH test provides an improved power over single-SNP based methods in detecting the prevalence of CH in human complex phenotypes, offering an opportunity for tackling the missing heritability problem. Binary and source packages of CollapsABEL are available on CRAN (https://cran.r-project.org/web/packages/CollapsABEL) and the website of the GenABEL project (http://www.genabel.org/packages)

Genome-wide compound heterozygote analysis highlights alleles associated with adult height in Europeans

Adult height is the most widely genetically studied common trait in humans; however, the trait variance explainable by currently known height-associated single nucleotide polymorphisms (SNPs) identified from the previous genome-wide association studies (GWAS) is yet far from complete given the high heritability of this complex trait. To exam if compound heterozygotes (CH) may explain extra height variance, we conducted a genome-wide analysis to screen for CH in association with adult height in 10,631 Dutch Europeans enriched with extremely tall people, using our recently developed method implemented in the software package CollapsABEL. The analysis identified six regions (3q23, 5q35.1, 6p21.31, 6p21.33, 7q21.2, and 9p24.3), where multiple pairs of SNPs as CH showed genome-wide significant association with height (P < 1.67 × 10−10). Of those, 9p24.3 represents a novel region influencing adult height, whereas the others have been highlighted in the previous GWAS on height based on analysis of individual SNPs. A replication analysis in 4080 Australians of European ancestry confirmed the significant CH-like association at 9p24.3 (P < 0.05). Together, the collapsed genotypes at these six loci explained 2.51% of the height variance (after adjusting for sex and age), compared with 3.23% explained by the 14 top-associated SNPs at 14 loci identified by traditional GWAS in the same data set (P < 5 × 10−8). Overall, our study empirically demonstrates that CH plays an important role in adult height and may explain a proportion of its “missing heritability”. Moreover, our findings raise promising expectations for other highly polygenic complex traits to explain missing heritability identifiable through CH-like associations

Genetics of skin color variation in Europeans: genome-wide association studies with functional follow-up

In the International Visible Trait Genetics (VisiGen) Consortium, we investigated the genetics of human skin color by combining a series of genome-wide association studies (GWAS) in a total of 17,262 Europeans with functional follow-up of discovered loci. Our GWAS provide the first genome-wide significant evidence for chromosome 20q11.22 harboring the ASIP gene being explicitly associated with skin color in Europeans. In addition, genomic loci at 5p13.2 (SLC45A2), 6p25.3 (IRF4), 15q13.1 (HERC2/OCA2), and 16q24.3 (MC1R) were confirmed to be involved in skin coloration in Europeans. In follow-up gene expression and regulation studies of 22 genes in 20q11.22, we highlighted two novel genes EIF2S2 and GSS, serving as competing functional candidates in this region and providing future research lines. A genetically inferred skin color score obtained from the 9 top-associated SNPs from 9 genes in 940 worldwide samples (HGDP-CEPH) showed a clear gradual pattern in Western Eurasians similar to the distribution of physical skin color, suggesting the used 9 SNPs as suitable markers for DNA prediction of skin color in Europeans and neighboring populations, relevant in future forensic and anthropological investigations

Genetics of skin color variation in Europeans: genome-wide association studies with functional follow-up

In the International Visible Trait Genetics (VisiGen) Consortium, we investigated the genetics of human skin color by combining a series of genome-wide association studies (GWAS) in a total of 17,262 Europeans with functional follow-up of discovered loci. Our GWAS provide the first genome-wide significant evidence for chromosome 20q11.22 harboring the ASIP gene being explicitly associated with skin color in Europeans. In addition, genomic loci at 5p13.2 (SLC45A2), 6p25.3 (IRF4), 15q13.1 (HERC2/OCA2), and 16q24.3 (MC1R) were confirmed to be involved in skin coloration in Europeans. In follow-up gene expression and regulation studies of 22 genes in 20q11.22, we highlighted two novel genes EIF2S2 and GSS, serving as competing functional candidates in this region and providing future research lines. A genetically inferred skin color score obtained from the 9 top-associated SNPs from 9 genes in 940 worldwide samples (HGDP-CEPH) showed a clear gradual pattern in Western Eurasians similar to the distribution of physical skin color, suggesting the used 9 SNPs as suitable markers for DNA prediction of skin color in Europeans and neighboring populations, relevant in future forensic and anthropological investigations