Dataset Information

Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.

ABSTRACT: Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10^-3) and candidate genes from knockout mice (P = 5.2 × 10^-3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.

SUBMITTER: Flannick J

PROVIDER: S-EPMC6699738 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.

Flannick Jason J Mercader Josep M JM Fuchsberger Christian C Udler Miriam S MS Mahajan Anubha A Wessel Jennifer J Teslovich Tanya M TM Caulkins Lizz L Koesterer Ryan R Barajas-Olmos Francisco F Blackwell Thomas W TW Boerwinkle Eric E Brody Jennifer A JA Centeno-Cruz Federico F Chen Ling L Chen Siying S Contreras-Cubas Cecilia C Córdova Emilio E Correa Adolfo A Cortes Maria M DeFronzo Ralph A RA Dolan Lawrence L Drews Kimberly L KL Elliott Amanda A Floyd James S JS Gabriel Stacey S Garay-Sevilla Maria Eugenia ME García-Ortiz Humberto H Gross Myron M Han Sohee S Heard-Costa Nancy L NL Jackson Anne U AU Jørgensen Marit E ME Kang Hyun Min HM Kelsey Megan M Kim Bong-Jo BJ Koistinen Heikki A HA Kuusisto Johanna J Leader Joseph B JB Linneberg Allan A Liu Ching-Ti CT Liu Jianjun J Lyssenko Valeriya V Manning Alisa K AK Marcketta Anthony A Malacara-Hernandez Juan Manuel JM Martínez-Hernández Angélica A Matsuo Karen K Mayer-Davis Elizabeth E Mendoza-Caamal Elvia E Mohlke Karen L KL Morrison Alanna C AC Ndungu Anne A Ng Maggie C Y MCY O'Dushlaine Colm C Payne Anthony J AJ Pihoker Catherine C Post Wendy S WS Preuss Michael M Psaty Bruce M BM Vasan Ramachandran S RS Rayner N William NW Reiner Alexander P AP Revilla-Monsalve Cristina C Robertson Neil R NR Santoro Nicola N Schurmann Claudia C So Wing Yee WY Soberón Xavier X Stringham Heather M HM Strom Tim M TM Tam Claudia H T CHT Thameem Farook F Tomlinson Brian B Torres Jason M JM Tracy Russell P RP van Dam Rob M RM Vujkovic Marijana M Wang Shuai S Welch Ryan P RP Witte Daniel R DR Wong Tien-Yin TY Atzmon Gil G Barzilai Nir N Blangero John J Bonnycastle Lori L LL Bowden Donald W DW Chambers John C JC Chan Edmund E Cheng Ching-Yu CY Cho Yoon Shin YS Collins Francis S FS de Vries Paul S PS Duggirala Ravindranath R Glaser Benjamin B Gonzalez Clicerio C Gonzalez Ma Elena ME Groop Leif L Kooner Jaspal Singh JS Kwak Soo Heon SH Laakso Markku M Lehman Donna M DM Nilsson Peter P Spector Timothy D TD Tai E Shyong ES Tuomi Tiinamaija T Tuomilehto Jaakko J Wilson James G JG Aguilar-Salinas Carlos A CA Bottinger Erwin E Burke Brian B Carey David J DJ Chan Juliana C N JCN Dupuis Josée J Frossard Philippe P Heckbert Susan R SR Hwang Mi Yeong MY Kim Young Jin YJ Kirchner H Lester HL Lee Jong-Young JY Lee Juyoung J Loos Ruth J F RJF Ma Ronald C W RCW Morris Andrew D AD O'Donnell Christopher J CJ Palmer Colin N A CNA Pankow James J Park Kyong Soo KS Rasheed Asif A Saleheen Danish D Sim Xueling X Small Kerrin S KS Teo Yik Ying YY Haiman Christopher C Hanis Craig L CL Henderson Brian E BE Orozco Lorena L Tusié-Luna Teresa T Dewey Frederick E FE Baras Aris A Gieger Christian C Meitinger Thomas T Strauch Konstantin K Lange Leslie L Grarup Niels N Hansen Torben T Pedersen Oluf O Zeitler Philip P Dabelea Dana D Abecasis Goncalo G Bell Graeme I GI Cox Nancy J NJ Seielstad Mark M Sladek Rob R Meigs James B JB Rich Steve S SS Rotter Jerome I JI Altshuler David D Burtt Noël P NP Scott Laura J LJ Morris Andrew P AP Florez Jose C JC McCarthy Mark I MI Boehnke Michael M

Nature 20190522 7759

Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, ...[more]

PMID: 31118516

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Project description:BackgroundColorectal cancer (CRC) cases with an age of onset <40 years suggests a germline genetic cause. In total, 51 simplex cases were included to test the hypothesis of CRC as a mendelian trait caused by either heterozygous autosomal dominant or bi-allelic autosomal recessive pathogenic variants.MethodsThe cohort was whole exome sequenced (WES) at 100× coverage. Both a dominant- and recessive model were used for searching predisposing genetic factors. In addition, we assayed recessive variants of potential moderate risk that were enriched in our young-onset CRC cohort. Variants were filtered using a candidate cancer gene list or by selecting variants more likely to be pathogenic based on variant type (e.g., loss-of-function) or allele frequency.ResultsWe identified one pathogenic variant in PTEN in a patient subsequently confirmed to have a hereditary hamartoma tumor syndrome (Cowden syndrome) and one patient with a pathogenic heterozygous variant in PMS2 that was originally not identified by WES due to low quality reads resulting from pseudogenes. In addition, we identified three heterozygous candidate missense variants in known cancer susceptibility genes (BMPR1A, BRIP1, and SRC), three truncating variants in possibly novel cancer genes (CLSPN, SEC24B, SSH2) and four candidate missense variants in ACACA, NR2C2, INPP4A, and DIDO1. We also identify five possible autosomal recessive candidate genes: ATP10B, PKHD1, UGGT2, MYH13, TFF3.ConclusionTwo clear pathogenic variants were identified in patients that had not been identified clinically. Thus, the chance of detecting a hereditary cancer syndrome in patients with CRC at young age but without family history is 2/51 (4%) and therefore the clinical benefit of genetic testing in this patient group is low. Of note, using stringent filtering, we have identified a total of ten candidate heterozygous variants and five possibly biallelic autosomal recessive candidate genes that warrant further study.

Dataset Information

Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.

Publications

Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.

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