Rare Non-coding Variation Identified by Large Scale Whole Genome Sequencing Reveals Unexplained Heritability of Type 2 Diabetes

Type 2 diabetes is increasing in all ancestry groups 1 . Part of its genetic basis may reside among the rare (minor allele frequency <0.1%) variants that make up the vast majority of human genetic variation 2 . We analyzed high-coverage (mean depth 38.2x) whole genome sequencing from 9,639 individuals with T2D and 34,994 controls in the NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program 2 to show that rare, non-coding variants that are poorly captured by genotyping arrays or imputation panels contribute h 2 =53% (P=4.2×10 −5 ) to the genetic component of risk in the largest (European) ancestry subset. We coupled sequence variation with islet epigenomic signatures 3 to annotate and group rare variants with respect to gene expression 4 , chromatin state 5 and three-dimensional chromatin architecture 6 , and show that pancreatic islet regulatory elements contribute to T2D genetic risk (h 2 =8%, P=2.4×10 −3 ). We used islet annotation to create a non-coding framework for rare variant aggregation testing. This approach identified five loci containing rare alleles in islet regulatory elements that suggest novel biological mechanisms readily linked to hypotheses about variant-to-function. Large scale whole genome sequence analysis reveals the substantial contribution of rare, non-coding variation to the genetic architecture of T2D and highlights the value of tissue-specific regulatory annotation for variant-to-function discovery.