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Identifying potential causal effects of age at menarche: a Mendelian randomization phenome-wide association study

journal contribution
posted on 11.05.2020 by Maria C Magnus, Anna L Guyatt, Rebecca B Lawn, Annah B Wyss, Katerina Trajanoska, Leanne K Kupers, Fernando Rivadeneira, Martin D Tobin, Stephanie J London, Debbie A Lawlor, Louise AC Millard, Abigail Fraser
Background: Age at menarche has been associated with various health outcomes. We aimed to identify potential causal effects of age at menarche on health-related traits in a hypothesis-free manner. Methods: We conducted a Mendelian randomization phenome-wide association study (MR-pheWAS) of age at menarche with 17,893 health-related traits in UK Biobank (n = 181,318) using PHESANT. The exposure of interest was the genetic risk score for age at menarche. We conducted a second MR-pheWAS after excluding SNPs associated with BMI from the genetic risk score, to examine whether results might be due to the genetic overlap between age at menarche and BMI. We followed up a subset of health-related traits to investigate MR assumptions and seek replication in independent study populations. Results: Of the 17,893 tests performed in our MR-pheWAS, we identified 619 associations with the genetic risk score for age at menarche at a 5% false discovery rate threshold, of which 295 were below a Bonferroni-corrected P value threshold. These included potential effects of younger age at menarche on lower lung function, higher heel bone-mineral density, greater burden of psychosocial/mental health problems, younger age at first birth, higher risk of childhood sexual abuse, poorer cardiometabolic health, and lower physical activity. After exclusion of variants associated with BMI, the genetic risk score for age at menarche was related to 37 traits at a 5% false discovery rate, of which 29 were below a Bonferroni-corrected P value threshold. We attempted to replicate findings for bone-mineral density, lung function, neuroticism, and childhood sexual abuse using 5 independent cohorts/consortia. While estimates for lung function, higher bone-mineral density, neuroticism, and childhood sexual abuse in replication cohorts were consistent with UK Biobank estimates, confidence intervals were wide and often included the null. Conclusions: The genetic risk score for age at menarche was related to a broad range of health-related traits. Follow-up analyses indicated imprecise evidence of an effect of younger age at menarche on greater bone-mineral density, lower lung function, higher neuroticism score, and greater risk of childhood sexual abuse in the smaller replication samples available; hence, these findings need further exploration when larger independent samples become available.

Funding

This work was partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700. MCM, AF, RL, LACM, and DAL work at the Medical Research Council Integrative Epidemiology Unit at the University of Bristol which receives infrastructure funding from the UK MRC (MC_UU_00011/6). The contributions of AF and DAL were supported by the National Institute for Health Research Biomedical Research Centre at University Hospitals Bristol National Health Service Foundation Trust and the University of Bristol. MCM and AF are supported by a UK MRC fellowship (MR/M009351/1) awarded to AF. LACM is funded by a University of Bristol Vice-Chancellor’s Fellowship. DAL’s contribution is supported by the US National Institutes of Health (R01 DK10324) and a European Research Council Advanced Grant (DevelopObese; 669545); DAL is an NIHR Senior Investigator (NF-SI-0616-10102). SJL and ABW are supported by the Intramural Research Program of the NIH (NIEHS ZO1 ES49019 and for ABW contract no. HHSN273201800005I). UK Biobank has received funding from the UK Medical Research Council, Wellcome Trust, Department of Health, British Heart Foundation, Diabetes UK, Northwest Regional Development Agency, Scottish Government, and Welsh Assembly Government. The data collection in ALSPAC is supported by the UK MRC, the Wellcome Trust (grant ref: 102215/2/13/2), and the University of Bristol. Genetic analyses in ALSPAC were supported by the Wellcome Trust (WT088806). Genetic analyses of lung function in SpiroMeta were supported by the Wellcome Trust (WT202849) and UK MRC MR/N011317/1 and G0902313. Infrastructure for the CHARGE Consortium is supported by the NHLBI grant R01HL105756. K. T and F. R are supported by the Netherlands Scientific Organization (NWO) and ZonMW Project number: NW O/ZONMW-VIDI-0 16-136-367. The GEFOS Consortium (www.gefos.org) was funded by the European Commission (HEALTH-F2-2008-201865-GEFOS).

History

Citation

Magnus, M.C., Guyatt, A.L., Lawn, R.B. et al. Identifying potential causal effects of age at menarche: a Mendelian randomization phenome-wide association study. BMC Med 18, 71 (2020). https://doi.org/10.1186/s12916-020-01515-y

Version

VoR (Version of Record)

Published in

BMC MEDICINE

Volume

18

Issue

1

Pagination

71 (17)

Publisher

BMC

issn

1741-7015

eissn

1741-7015

Acceptance date

10/02/2020

Copyright date

2020

Available date

23/03/2020

Publisher version

https://link.springer.com/article/10.1186/s12916-020-01515-y

Spatial coverage

UK

Language

English

Licence

Exports