Abstract
Although recent Genome-Wide Association Studies have identified novel associations for common variants, there has been no comprehensive exome-wide search for low-frequency variants that affect the risk of venous thromboembolism (VTE). We conducted a meta-analysis of 11 studies comprising 8,332 cases and 16,087 controls of European ancestry and 382 cases and 1,476 controls of African American ancestry genotyped with the Illumina HumanExome BeadChip. We used the seqMeta package in R to conduct single variant and gene-based rare variant tests. In the single variant analysis, we limited our analysis to the 64,794 variants with at least 40 minor alleles across studies (minor allele frequency [MAF] ~0.08%). We confirmed associations with previously identified VTE loci, including ABO, F5, F11, and FGA. After adjusting for multiple testing, we observed no novel significant findings in single variant or gene-based analysis. Given our sample size, we had greater than 80% power to detect minimum odds ratios greater than 1.5 and 1.8 for a single variant with MAF of 0.01 and 0.005, respectively. Larger studies and sequence data may be needed to identify novel low-frequency and rare variants associated with VTE risk.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 449-457 |
| Number of pages | 9 |
| Journal | Genetic epidemiology |
| Volume | 43 |
| Issue number | 4 |
| DOIs | |
| State | Published - Jun 2019 |
Bibliographical note
Funding Information:Atherosclerosis Risk in Communities (ARIC): The ARIC study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, NIH, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN 268201700005I). The authors thank the staff and participants of the ARIC study for their important contributions. Funding for LITE was supported by R01HL59367. Funding support for “Building on GWAS for NHLBI‐diseases: the US CHARGE consortium” was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA; 5RC2HL102419). Cardiovascular Health Study (CHS): This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL 087652, R01HL105756, R01HL103612, R01HL120393, R01HL130114, and R01HL068986 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS‐NHLBI. org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC; Grant DK063491) to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Framingham Heart Study (FHS): The FHS is conducted and supported by the NHLBI in collaboration with Boston University (Contract No. N01‐HC‐25195). Genotyping, quality control, and calling of the Illumina HumanExome BeadChip in the FHS were supported by funding from the National Heart, Lung and Blood Institute Division of Intramural Research (Daniel Levy and Christopher J. O’Donnell, Principal Investigators). Support for the centralized genotype calling was provided by Building on GWAS for NHLBI‐diseases: the US CHARGE consortium through the National Institutes of Health (NIH) American Recovery and Reinvestment Act of 2009 (5RC2HL102419). M.H.C. and A.D.J. were supported by National Heart, Lung and Blood Institute Division of Intramural Research funds. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the US Department of Health and Human Services. HVH: The research of the Heart and Vascular Health Studies has been funded in part by National Institute of Health grants HL040628, HL043201, HL053375, HL060739, HL68639, HL068986, HL073410, HL74745, HL085251, HL095080. MARTHA genetics project was supported by the GENMED Laboratory of Excellence on Medical Genomics (ANR‐10‐LABX‐0013), the French Clinical Research Infrastructure Network on Venous Thrombo‐Embolism (F‐CRIN INNOVTE) and the ICAN Institute for Cardiometabolism and Nutrition (ANR‐10‐ IAHU), three research programs managed by the National Research Agency (ANR) part of the French Investment for the Future initiative. NHS/NHSII/HPFS: These studies received grant supports P01CA87969, R01CA49449, R01HL034594, R01HL088521, R01CA50385, R01CA67262, P01CA055075, R01HL35464, R01HL116854. We thank all of the researchers and staff whose hard work made each of the contributing studies possible. Tromsø: This study was supported by an independent grant from Stiftelsen Kristian Gerhard Jebsen in Norway. WGHS: The Women’s Genome Health Study is funded by the National Heart, Lung, and Blood Institute (HL043851, HL080467, and HL099355) and the National Cancer Institute (CA047988 and UM1CA182913), with support for genotyping provided by Amgen. WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN 268201600003C, and HHSN268201600004C.
Funding Information:
Atherosclerosis Risk in Communities (ARIC): The ARIC study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, NIH, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I and HHSN268201700005I). The authors thank the staff and participants of the ARIC study for their important contributions. Funding for LITE was supported by R01HL59367. Funding support for ?Building on GWAS for NHLBI-diseases: the US CHARGE consortium? was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA; 5RC2HL102419). Cardiovascular Health Study (CHS): This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, R01HL130114, and R01HL068986 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC; Grant DK063491) to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Framingham Heart Study (FHS): The FHS is conducted and supported by the NHLBI in collaboration with Boston University (Contract No. N01-HC-25195). Genotyping, quality control, and calling of the Illumina HumanExome BeadChip in the FHS were supported by funding from the National Heart, Lung and Blood Institute Division of Intramural Research (Daniel Levy and Christopher J. O?Donnell, Principal Investigators). Support for the centralized genotype calling was provided by Building on GWAS for NHLBI-diseases: the US CHARGE consortium through the National Institutes of Health (NIH) American Recovery and Reinvestment Act of 2009 (5RC2HL102419). M.H.C. and A.D.J. were supported by National Heart, Lung and Blood Institute Division of Intramural Research funds. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the US Department of Health and Human Services. HVH: The research of the Heart and Vascular Health Studies has been funded in part by National Institute of Health grants HL040628, HL043201, HL053375, HL060739, HL68639, HL068986, HL073410, HL74745, HL085251, HL095080. MARTHA genetics project was supported by the GENMED Laboratory of Excellence on Medical Genomics (ANR-10-LABX-0013), the French Clinical Research Infrastructure Network on Venous Thrombo-Embolism (F-CRIN INNOVTE) and the ICAN Institute for Cardiometabolism and Nutrition (ANR-10-IAHU), three research programs managed by the National Research Agency (ANR) part of the French Investment for the Future initiative. NHS/NHSII/HPFS: These studies received grant supports P01CA87969, R01CA49449, R01HL034594, R01HL088521, R01CA50385, R01CA67262, P01CA055075, R01HL35464, R01HL116854. We thank all of the researchers and staff whose hard work made each of the contributing studies possible. Troms?: This study was supported by an independent grant from Stiftelsen Kristian Gerhard Jebsen in Norway. WGHS: The Women?s Genome Health Study is funded by the National Heart, Lung, and Blood Institute (HL043851, HL080467, and HL099355) and the National Cancer Institute (CA047988 and UM1CA182913), with support for genotyping provided by Amgen. WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C.
Publisher Copyright:
© 2019 Wiley Periodicals, Inc.
Keywords
- exome
- genetic association
- venous thromboembolism