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Genetic associations with age of menopause in familial longevity

Bae, Harold PhD1; Lunetta, Kathryn L. PhD2; Murabito, Joanne M. MD3; Andersen, Stacy L. PhD4; Schupf, Nicole PhD5; Perls, Thomas MD, MPH4; Sebastiani, Paola PhD2 on behalf of the Long Life Family Study

doi: 10.1097/GME.0000000000001367
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Objective: We hypothesize that mechanisms associated with extended reproductive age may overlap with mechanisms for the selection of genetic variants that slow aging and decrease risk for age-related diseases. Therefore, the goal of this analysis is to search for genetic variants associated with delayed age of menopause (AOM) among women in a study of familial longevity.

Methods: We performed a meta-analysis of genome-wide association studies for AOM in 1,286 women in the Long Life Family Study (LLFS) and 3,151 women in the Health and Retirement Study, and then sought replication in the Framingham Heart Study (FHS). We used Cox proportional hazard regression of AOM to account for censoring, with a robust variance estimator to adjust for within familial relations.

Results: In the meta-analysis, a single nucleotide polymorphism (SNP) previously associated with AOM reached genome-wide significance (rs16991615; HR = 0.74, P = 6.99 × 10−12). A total of 35 variants reached >10−4 level of significance and replicated in the FHS and in a 2015 large meta-analysis (ReproGen Consortium). We also identified several novel SNPs associated with AOM including rs3094005: MICB, rs13196892: TXNDC5 | MUTED, rs72774935: SSBP2 | ATG10, rs9447453: COL12A1, rs114298934: FHL2 | NCK2, rs6467223: TNPO3, rs9666274 and rs10766593: NAV2, and rs7281846: HSPA13.

Conclusions: This work indicates novel associations and replicates known associations between genetic variants and AOM. A number of these associations make sense for their roles in aging.

Video Summary: Supplemental Digital Content 1, http://links.lww.com/MENO/A420.

1College of Public Health and Human Sciences, Oregon State University, Corvallis, OR

2Department of Biostatistics, Boston University School of Public Health, Boston, MA

3Section of General Internal Medicine, Department of Medicine, and the Framingham Heart Study, Boston University School of Medicine, Boston, MA

4Geriatrics Section, Department of Medicine, Boston Medical Center and Boston University School of Medicine, Boston, MA

5Department of Epidemiology, Mailman School of Public Health, Columbia University, NY.

Address correspondence to: Harold Bae, PhD, 161 Milam Hall, School of Biological and Population Health Sciences, College of Public Health and Human Sciences, Oregon State University, Corvallis, OR 97331. E-mail: harold.bae@oregonstate.edu

Received 15 February, 2019

Revised 11 April, 2019

Accepted 11 April, 2019

Funding/support: This work was supported by the National Institute on Aging (NIA cooperative agreements U01-AG023712, U01-AG23744, U01-AG023746, U01-AG023749, and U01-AG023755) as well as NIA funded grants: U19-AG023122 TP, and R21AG056630 PS. Funding also provided by a National Institute of General Medical (NIGMS) Interdisciplinary Training Grant for Biostatisticians [T32 GM74905], the William M. Wood Foundation (TP), and the Paulette and Marty Samowitz Family Foundation (TP). The Health and Retirement Study, whose data we used through dbGaP, is funded by the National Institute on Aging (grant numbers U01AG009740, RC2AG036495, and RC4AG039029) and is conducted by the University of Michigan.

Financial disclosure/conflicts of interest: None reported.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.menopause.org).

© 2019 by The North American Menopause Society.