Dataset Information

Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.

ABSTRACT: Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

SUBMITTER: Wessel J

PROVIDER: S-EPMC4311266 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.

Wessel Jennifer J Chu Audrey Y AY Willems Sara M SM Wang Shuai S Yaghootkar Hanieh H Brody Jennifer A JA Dauriz Marco M Hivert Marie-France MF Raghavan Sridharan S Lipovich Leonard L Hidalgo Bertha B Fox Keolu K Huffman Jennifer E JE An Ping P Lu Yingchang Y Rasmussen-Torvik Laura J LJ Grarup Niels N Ehm Margaret G MG Li Li L Baldridge Abigail S AS Stančáková Alena A Abrol Ravinder R Besse Céline C Boland Anne A Bork-Jensen Jette J Fornage Myriam M Freitag Daniel F DF Garcia Melissa E ME Guo Xiuqing X Hara Kazuo K Isaacs Aaron A Jakobsdottir Johanna J Lange Leslie A LA Layton Jill C JC Li Man M Hua Zhao Jing J Meidtner Karina K Morrison Alanna C AC Nalls Mike A MA Peters Marjolein J MJ Sabater-Lleal Maria M Schurmann Claudia C Silveira Angela A Smith Albert V AV Southam Lorraine L Stoiber Marcus H MH Strawbridge Rona J RJ Taylor Kent D KD Varga Tibor V TV Allin Kristine H KH Amin Najaf N Aponte Jennifer L JL Aung Tin T Barbieri Caterina C Bihlmeyer Nathan A NA Boehnke Michael M Bombieri Cristina C Bowden Donald W DW Burns Sean M SM Chen Yuning Y Chen Yii-DerI YD Cheng Ching-Yu CY Correa Adolfo A Czajkowski Jacek J Dehghan Abbas A Ehret Georg B GB Eiriksdottir Gudny G Escher Stefan A SA Farmaki Aliki-Eleni AE Frånberg Mattias M Gambaro Giovanni G Giulianini Franco F Goddard William A WA Goel Anuj A Gottesman Omri O Grove Megan L ML Gustafsson Stefan S Hai Yang Y Hallmans Göran G Heo Jiyoung J Hoffmann Per P Ikram Mohammad K MK Jensen Richard A RA Jørgensen Marit E ME Jørgensen Torben T Karaleftheri Maria M Khor Chiea C CC Kirkpatrick Andrea A Kraja Aldi T AT Kuusisto Johanna J Lange Ethan M EM Lee I T IT Lee Wen-Jane WJ Leong Aaron A Liao Jiemin J Liu Chunyu C Liu Yongmei Y Lindgren Cecilia M CM Linneberg Allan A Malerba Giovanni G Mamakou Vasiliki V Marouli Eirini E Maruthur Nisa M NM Matchan Angela A McKean-Cowdin Roberta R McLeod Olga O Metcalf Ginger A GA Mohlke Karen L KL Muzny Donna M DM Ntalla Ioanna I Palmer Nicholette D ND Pasko Dorota D Peter Andreas A Rayner Nigel W NW Renström Frida F Rice Ken K Sala Cinzia F CF Sennblad Bengt B Serafetinidis Ioannis I Smith Jennifer A JA Soranzo Nicole N Speliotes Elizabeth K EK Stahl Eli A EA Stirrups Kathleen K Tentolouris Nikos N Thanopoulou Anastasia A Torres Mina M Traglia Michela M Tsafantakis Emmanouil E Javad Sundas S Yanek Lisa R LR Zengini Eleni E Becker Diane M DM Bis Joshua C JC Brown James B JB Cupples L Adrienne LA Hansen Torben T Ingelsson Erik E Karter Andrew J AJ Lorenzo Carlos C Mathias Rasika A RA Norris Jill M JM Peloso Gina M GM Sheu Wayne H-H WH Toniolo Daniela D Vaidya Dhananjay D Varma Rohit R Wagenknecht Lynne E LE Boeing Heiner H Bottinger Erwin P EP Dedoussis George G Deloukas Panos P Ferrannini Ele E Franco Oscar H OH Franks Paul W PW Gibbs Richard A RA Gudnason Vilmundur V Hamsten Anders A Harris Tamara B TB Hattersley Andrew T AT Hayward Caroline C Hofman Albert A Jansson Jan-Håkan JH Langenberg Claudia C Launer Lenore J LJ Levy Daniel D Oostra Ben A BA O'Donnell Christopher J CJ O'Rahilly Stephen S Padmanabhan Sandosh S Pankow James S JS Polasek Ozren O Province Michael A MA Rich Stephen S SS Ridker Paul M PM Rudan Igor I Schulze Matthias B MB Smith Blair H BH Uitterlinden André G AG Walker Mark M Watkins Hugh H Wong Tien Y TY Zeggini Eleftheria E Laakso Markku M Borecki Ingrid B IB Chasman Daniel I DI Pedersen Oluf O Psaty Bruce M BM Tai E Shyong ES van Duijn Cornelia M CM Wareham Nicholas J NJ Waterworth Dawn M DM Boerwinkle Eric E Kao W H Linda WH Florez Jose C JC Loos Ruth J F RJ Wilson James G JG Frayling Timothy M TM Siscovick David S DS Dupuis Josée J Rotter Jerome I JI Meigs James B JB Scott Robert A RA Goodarzi Mark O MO

Nature communications 20150129

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretio ...[more]

PMID: 25631608

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Project description:Background and Purpose- White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. Methods- In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. Results- At 17q25, we confirmed the association of multiple common variants in TRIM65, FBF1, and ACOX1 ( P<6×10-7). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221; PEA=4.5×10-8) partially independent of known common signal ( PEA(conditional)=1.4×10-3). We further identified a locus at 2q33 containing common variants in NBEAL1, CARF, and WDR12 (lead, rs2351524; Pall=1.9×10-10). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency MRPL38 variants ( Prs34136221=2.8×10-8). Conclusions- Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.

Project description:Copy number variants (CNVs) are a major source of genetic variation and can disrupt genes or affect gene dosage. They are known to be causal or underlie predisposition to various diseases. However, the role of CNVs in inherited breast cancer susceptibility has not been thoroughly investigated. To address this, we performed whole-exome sequencing based analysis of rare CNVs in 98 high-risk Northern Finnish breast cancer cases. After filtering, selected candidate alleles were validated and characterized with a combination of orthogonal methods, including PCR-based approaches, optical genome mapping and long-read sequencing. This revealed three recurrent alterations: a 31 kb deletion co-occurring with a retrotransposon insertion (delins) in RAD52, a 13.4 kb deletion in HSD17B14 and a 64 kb partial duplication of RAD51C. Notably, all these genes encode proteins involved in pathways previously identified as essential for breast cancer development. Variants were genotyped in geographically matched cases and controls (altogether 278 hereditary and 1983 unselected breast cancer cases, and 1229 controls). The RAD52 delins and HSD17B14 deletion both showed significant enrichment among cases with indications of hereditary disease susceptibility. RAD52 delins was identified in 7/278 cases (2.5%, P = 0.034, OR = 2.86, 95% CI = 1.10-7.45) and HSD17B14 deletion in 8/278 cases (2.9%, P = 0.014, OR = 3.28, 95% CI = 1.31-8.23), the frequency of both variants in the controls being 11/1229 (0.9%). This suggests a role for RAD52 and HSD17B14 in hereditary breast cancer susceptibility. The RAD51C duplication was very rare, identified only in 2/278 of hereditary cases and 2/1229 controls (P = 0.157, OR = 4.45, 95% CI = 0.62-31.70). The identification of recurrent CNVs in these genes, and especially the relatively high frequency of RAD52 and HSD17B14 alterations in the Finnish population, highlights the importance of studying CNVs alongside single nucleotide variants when searching for genetic factors underlying hereditary disease predisposition.

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Dataset Information

Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.

Publications

Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.

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