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Genome-wide association studies are designed to discover SNPs that are associated with a complex trait. Employing strict significance thresholds when testing individual SNPs avoids false positives at the expense of increasing false negatives. Recently, we developed a method for quantitative traits that estimates the variation accounted for when fitting all SNPs simultaneously. Here we develop this method further for case-control studies. We use a linear mixed model for analysis of binary traits and transform the estimates to a liability scale by adjusting both for scale and for ascertainment of the case samples. We show by theory and simulation that the method is unbiased. We apply the method to data from the Wellcome Trust Case Control Consortium and show that a substantial proportion of variation in liability for Crohn disease, bipolar disorder, and type I diabetes is tagged by common SNPs. [ABSTRACT FROM AUTHOR]

Across species, offspring of related individuals often exhibit significant reduction in fitness-related traits, known as inbreeding depression (ID), yet the genetic and molecular basis for ID remains elusive. Here, we develop a method to quantify enrichment of ID within specific genomic annotations and apply it to human data. We analyzed the phenomes and genomes of ∼350,000 unrelated participants of the UK Biobank and found, on average of over 11 traits, significant enrichment of ID within genomic regions with high recombination rates (>21-fold; p < 10−5), with conserved function across species (>19-fold; p < 10−4), and within regulatory elements such as DNase I hypersensitive sites (∼5-fold; p = 8.9 × 10−7). We also quantified enrichment of ID within trait-associated regions and found suggestive evidence that genomic regions contributing to additive genetic variance in the population are enriched for ID signal. We find strong correlations between functional enrichment of SNP-based heritability and that of ID (r = 0.8, standard error: 0.1). These findings provide empirical evidence that ID is most likely due to many partially recessive deleterious alleles in low linkage disequilibrium regions of the genome. Our study suggests that functional characterization of ID may further elucidate the genetic architectures and biological mechanisms underlying complex traits and diseases. [ABSTRACT FROM AUTHOR]