Dataset Information

Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk.

ABSTRACT: Rare and low frequency variants are not well covered in most germline genotyping arrays and are understudied in relation to epithelial ovarian cancer (EOC) risk. To address this gap, we used genotyping arrays targeting rarer protein-coding variation in 8,165 EOC cases and 11,619 controls from the international Ovarian Cancer Association Consortium (OCAC). Pooled association analyses were conducted at the variant and gene level for 98,543 variants directly genotyped through two exome genotyping projects. Only common variants that represent or are in strong linkage disequilibrium (LD) with previously-identified signals at established loci reached traditional thresholds for exome-wide significance (P??P?5.0 ×10?-? 7) were detected for rare and low-frequency variants at 16 novel loci. Four rare missense variants were identified (ACTBL2 rs73757391 (5q11.2), BTD rs200337373 (3p25.1), KRT13 rs150321809 (17q21.2) and MC2R rs104894658 (18p11.21)), but only MC2R rs104894668 had a large effect size (OR?=?9.66). Genes most strongly associated with EOC risk included ACTBL2 (PAML?=?3.23 × 10?-? 5; PSKAT-o?=?9.23?×?10?-? 4) and KRT13 (PAML?=?1.67 × 10?-? 4; PSKAT-o?=?1.07?×?10?-? 5), reaffirming variant-level analysis. In summary, this large study identified several rare and low-frequency variants and genes that may contribute to EOC susceptibility, albeit with possible small effects. Future studies that integrate epidemiology, sequencing, and functional assays are needed to further unravel the unexplained heritability and biology of this disease.

SUBMITTER: Permuth JB

PROVIDER: S-EPMC5179948 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk.

Permuth Jennifer B JB Pirie Ailith A Ann Chen Y Y Lin Hui-Yi HY Reid Brett M BM Chen Zhihua Z Monteiro Alvaro A Dennis Joe J Mendoza-Fandino Gustavo G Anton-Culver Hoda H Bandera Elisa V EV Bisogna Maria M Brinton Louise L Brooks-Wilson Angela A Carney Michael E ME Chenevix-Trench Georgia G Cook Linda S LS Cramer Daniel W DW Cunningham Julie M JM Cybulski Cezary C D'Aloisio Aimee A AA Anne Doherty Jennifer J Earp Madalene M Edwards Robert P RP Fridley Brooke L BL Gayther Simon A SA Gentry-Maharaj Aleksandra A Goodman Marc T MT Gronwald Jacek J Hogdall Estrid E Iversen Edwin S ES Jakubowska Anna A Jensen Allan A Karlan Beth Y BY Kelemen Linda E LE Kjaer Suzanne K SK Kraft Peter P Le Nhu D ND Levine Douglas A DA Lissowska Jolanta J Lubinski Jan J Matsuo Keitaro K Menon Usha U Modugno Rosemary R Moysich Kirsten B KB Nakanishi Toru T Ness Roberta B RB Olson Sara S Orlow Irene I Pearce Celeste L CL Pejovic Tanja T Poole Elizabeth M EM Ramus Susan J SJ Anne Rossing Mary M Sandler Dale P DP Shu Xiao-Ou XO Song Honglin H Taylor Jack A JA Teo Soo-Hwang SH Terry Kathryn L KL Thompson Pamela J PJ Tworoger Shelley S SS Webb Penelope M PM Wentzensen Nicolas N Wilkens Lynne R LR Winham Stacey S Woo Yin-Ling YL Wu Anna H AH Yang Hannah H Zheng Wei W Ziogas Argyrios A Phelan Catherine M CM Schildkraut Joellen M JM Berchuck Andrew A Goode Ellen L EL Pharoah Paul D P PD Sellers Thomas A TA

Human molecular genetics 20160704 16

Rare and low frequency variants are not well covered in most germline genotyping arrays and are understudied in relation to epithelial ovarian cancer (EOC) risk. To address this gap, we used genotyping arrays targeting rarer protein-coding variation in 8,165 EOC cases and 11,619 controls from the international Ovarian Cancer Association Consortium (OCAC). Pooled association analyses were conducted at the variant and gene level for 98,543 variants directly genotyped through two exome genotyping p ...[more]

PMID: 27378695

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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.

Dataset Information

Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk.

Publications

Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk.

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