Rare genetic variants contribute to complex disease risk; however, the abundance of rare variants in human populations remains unknown. We explored this spectrum of variation by sequencing 202 genes encoding drug targets in 14,002 individuals. We find rare variants are abundant (one every 17 bases) and geographically localized, such that even with large sample sizes, rare variant catalogs will be largely incomplete. We used the observed patterns of variation to estimate population growth parameters, the proportion of variants in a given frequency class that are putatively deleterious, and mutation rates for each gene. Overall we conclude that, due to rapid population growth and weak purifying selection, human populations harbor an abundance of rare variants, many of which are deleterious and have relevance to understanding disease risk.

Psoriasis is a complex disease of skin with a prevalence of about 2%. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for psoriasis to date, including data from eight different Caucasian cohorts, with a combined effective sample size >39,000 individuals. We identified 16 additional psoriasis susceptibility loci achieving genome-wide significance, increasing the number of identified loci to 63 for European-origin individuals. Functional analysis highlighted the roles of interferon signalling and the NFκB cascade, and we showed that the psoriasis signals are enriched in regulatory elements from different T cells (CD8+ T-cells and CD4+ T-cells including TH0, TH1 and TH17). The identified loci explain ∼28% of the genetic heritability and generate a discriminatory genetic risk score (AUC=0.76 in our sample) that is significantly correlated with age at onset (p=2 × 10−89). This study provides a comprehensive layout for the genetic architecture of common variants for psoriasis.

The vast majority of connections between complex disease and common genetic variants were identified through meta-analysis, a powerful approach that enables large sample sizes while protecting against common artifacts due to population structure, repeated small sample analyses, and/or limitations with sharing individual level data. As the focus of genetic association studies shifts to rare variants, genes and other functional units are becoming the unit of analysis. Here, we propose and evaluate new approaches for performing meta-analysis of rare variant association tests, including burden tests, weighted burden tests, variable threshold tests and tests that allow variants with opposite effects to be grouped together. We show that our approach retains useful features of single variant meta-analytic approaches and demonstrate its utility in a study of blood lipid levels in ∼18,500 individuals genotyped with exome arrays.

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 melanoma cases (67% newly-genotyped) and 375,188 controls identified 54 significant loci with 68 independent SNPs. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with nevus count and hair color GWAS, and transcriptome association approaches, uncovered 31 potential secondary loci, for a total of 85 cutaneous melanoma susceptibility loci. These findings provide substantial insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation, and telomere maintenance together with identifying potential new pathways for cutaneous melanoma pathogenesis.

A detailed understanding of the genome-wide variability of single-nucleotide germline mutation rates is essential to studying human genome evolution. Here, we use ~36 million singleton variants from 3560 whole-genome sequences to infer fine-scale patterns of mutation rate heterogeneity. Mutability is jointly affected by adjacent nucleotide context and diverse genomic features of the surrounding region, including histone modifications, replication timing, and recombination rate, sometimes suggesting specific mutagenic mechanisms. Remarkably, GC content, DNase hypersensitivity, CpG islands, and H3K36 trimethylation are associated with both increased and decreased mutation rates depending on nucleotide context. We validate these estimated effects in an independent dataset of ~46,000 de novo mutations, and confirm our estimates are more accurate than previously published results based on ancestrally older variants without considering genomic features. Our results thus provide the most refined portrait to date of the factors contributing to genome-wide variability of the human germline mutation rate.