Altshuler, D. | Search bioRxiv

bioRxiv2018

Genetic discovery and translational decision support from exome sequencing of 20,791 type 2 diabetes cases and 24,440 controls from five ancestries

Protein-coding genetic variants that strongly affect disease risk can provide important clues into disease pathogenesis. Here we report an exome sequence analysis of 20,791 type 2 diabetes (T2D) cases and 24,440 controls from five ancestries. We identify rare (minor allele frequency<0.5%) variant gene-level associations in (a) three genes at exome-wide significance, including a T2D-protective series of >30 SLC30A8 alleles, and (b) within 12 gene sets, including those corresponding to T2D drug targets (p=6.1x10-3) and candidate genes from knockout mice (p=5.2x10-3). Within our study, the strongest T2D rare variant gene-level signals explain at most 25% of the heritability of the strongest common single-variant signals, and the rare variant gene-level effect sizes we observe in established T2D drug targets will require 110K-180K sequenced cases to exceed exome-wide significance. To help prioritize genes using associations from current smaller sample sizes, we present a Bayesian framework to recalibrate association p-values as posterior probabilities of association, estimating that reaching p<0.05 (p<0.005) in our study increases the odds of causal T2D association for a nonsynonymous variant by a factor of 1.8 (5.3). To help guide target or gene prioritization efforts, our data are freely available for analysis at www.type2diabetesgenetics.org.

genetics↗

bioRxiv2017

A Strategy for Large-Scale Systematic Pan-Cancer Germline Rare Variation Analysis

Traditionally, genetic studies in cancer are focused on somatic mutations found in tumors and absent from the normal tissue. Identification of shared attributes in germline variation could aid discrimination of high-risk from likely benign mutations and narrow the search space for new cancer predisposing genes. Extraordinary progress made in analysis of common variation with GWAS methodology does not provide sufficient resolution to understand rare variation. To fulfil missing classification for rare germline variation we assembled datasets of whole exome sequences from >2,000 patients with different types of cancers: breast cancer, colon cancer and cutaneous and ocular melanomas matched to more than 7,000 non-cancer controls and analyzed germline variation in known cancer predisposing genes to identify common properties of disease associated mutations and new candidate cancer susceptibility genes. Lists of all cancer predisposing genes were divided into subclasses according to the mode of inheritance of the related cancer syndrome or contribution to known major cancer pathways. Out of all subclasses only genes linked to dominant syndromes presented significant rare germline variants enrichment in cases. Separate analysis of protein-truncating and missense variation in this subclass of genes confirmed significant prevalence of protein-truncating variants in cases only in loss-of-function tolerant genes (pLI<0.1), while ultra-rare missense mutations were significantly overrepresented in cases only in constrained genes (pLI>0.9). Taken together, our findings provide insights into the distribution and types of mutations underlying inherited cancer predisposition.

genetics↗