Rare Non-coding Variation Identified by Large Scale Whole Genome Sequencing Reveals Unexplained Heritability of Type 2 Diabetes
Authors: Wessel Jennifer , Majarian Timothy D , Highland Heather M , Raghavan Sridharan , Szeto Mindy D , Hasbani Natalie R , de Vries Paul S , Brody Jennifer A , Sarnowski Chloé , DiCorpo Daniel , Yin Xianyong , Hidalgo Bertha , Guo Xiuqing , Perry James , O’Connell Jeffrey R , Lent Samantha , Montasser May E , Cade Brian E , Jain Deepti , Wang Heming , Wu Peitao , Bonàs-Guarch Silvia , D’Oliveira Albanus Ricardo , Leong Aaron , Miguel-Escalada Irene , Varshney Arushi ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Anthropometry, DIAMANTE, Kinney Gregory L , Yanek Lisa R , Lange Leslie , Almeida Marcio , Peralta Juan M , Aslibekyan Stella , Baldridge Abigail S , Bertoni Alain G , Bielak Lawrence F , Bowden Donald W , Chen Chung-Shiuan , Chen Yii-Der Ida , Choi Seung Hoan , Choi Won Jung , Darbar Dawood , Floyd James S , Freedman Barry I , Goodarzi Mark O , Irvin Ryan , Kalyani Rita R , Kelly Tanika , Lee Seonwook , Liu Ching-Ti , Loesch Douglas , Manson JoAnn E , Nassir Rami , Palmer Nicholette D , Pankow James S , Rasmussen-Torvik Laura J , Reiner Alexander P , Selvin Elizabeth , Shadyab Aladdin H , Smith Jennifer A , Weeks Daniel E , Weng Lu-Chen , Xu Huichun , Yao Jie , Yoneda Zachary , Zhao Wei , Ferrer Jorge , Mahajan Anubha , McCarthy Mark I , Parker Stephen , Alonso Alvaro , Arnett Donna K , Blangero John , Boerwinkle Eric , Cho Michael H , Correa Adolfo , Cupples L. Adrienne , Curran Joanne E , Duggirala Ravindranath , Ellinor Patrick T , He Jiang , Heckbert Susan R , Kardia Sharon LR , Kim Ryan W , Kooperberg Charles , Liu Simin , Lubitz Steven A , Mathias Rasika A , McGarvey Stephen , Mitchell Braxton D , Morrison Alanna C , Peyser Patricia A , Psaty Bruce M , Redline Susan , Roden Dan , Shoemaker M. Benjamin , Smith Nicholas L , Taylor Kent D , Vasan Ramachandran S , Viaud-Martinez Karine A , Florez Jose C , Wilson James G , Sladek Robert , Dupuis Josée , Rich Stephen S , Rotter Jerome I , Meigs James B , Manning Alisa K 
Published: November 2020

Type 2 diabetes is increasing in all ancestry groups1. 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 variation2. 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) program2 to show that rare, non-coding variants that are poorly captured by genotyping arrays or imputation panels contribute h2=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 signatures3 to annotate and group rare variants with respect to gene expression4, chromatin state5 and three-dimensional chromatin architecture6, and show that pancreatic islet regulatory elements contribute to T2D genetic risk (h2=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.