2381/12264929.v2
Maria C Magnus
Maria C
Magnus
Anna L Guyatt
Anna L
Guyatt
Rebecca B Lawn
Rebecca B
Lawn
Annah B Wyss
Annah B
Wyss
Katerina Trajanoska
Katerina
Trajanoska
Leanne K Kupers
Leanne K
Kupers
Fernando Rivadeneira
Fernando
Rivadeneira
Martin D Tobin
Martin D
Tobin
Stephanie J London
Stephanie J
London
Debbie A Lawlor
Debbie A
Lawlor
Louise AC Millard
Louise AC
Millard
Abigail Fraser
Abigail
Fraser
Identifying potential causal effects of age at menarche: a Mendelian randomization phenome-wide association study
University of Leicester
2020
Science & Technology
Life Sciences & Biomedicine
Medicine, General & Internal
General & Internal Medicine
Menarche
Mendelian randomization
MR-pheWAS
METAANALYSIS
RISK
TOOL
INSTRUMENTS
NEUROTICISM
DEPRESSION
IMPUTATION
VARIANTS
CANCER
LOCI
2020-05-11 09:35:03
Journal contribution
https://figshare.le.ac.uk/articles/journal_contribution/Identifying_potential_causal_effects_of_age_at_menarche_a_Mendelian_randomization_phenome-wide_association_study/12264929
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.