Abstract
Estimates from Mendelian randomization studies of unrelated individuals can be biased due to uncontrolled confounding from familial effects. Here we describe methods for within-family Mendelian randomization analyses and use simulation studies to show that family-based analyses can reduce such biases. We illustrate empirically how familial effects can affect estimates using data from 61,008 siblings from the Nord-Trøndelag Health Study and UK Biobank and replicated our findings using 222,368 siblings from 23andMe. Both Mendelian randomization estimates using unrelated individuals and within family methods reproduced established effects of lower BMI reducing risk of diabetes and high blood pressure. However, while Mendelian randomization estimates from samples of unrelated individuals suggested that taller height and lower BMI increase educational attainment, these effects were strongly attenuated in within-family Mendelian randomization analyses. Our findings indicate the necessity of controlling for population structure and familial effects in Mendelian randomization studies.
| Original language | English |
|---|---|
| Article number | 3519 |
| Pages (from-to) | 1-13 |
| Number of pages | 13 |
| Journal | Nature Communications |
| Volume | 11 |
| Issue number | 1 |
| Early online date | 14 Jul 2020 |
| DOIs | |
| Publication status | Published - 1 Dec 2020 |
Funding
Jonathan Beauchamp provided valuable comments and suggestions on an earlier draft of this paper. This research has been conducted using the UK Biobank Resource under Application Number 16729. Quality Control filtering of the UK Biobank data was conducted by R.Mitchell, G.Hemani, T.Dudding, L.Paternoster as described in the published protocol (doi:10.5523/bris.3074krb6t2frj29yh2b03x3wxj). The MRC IEU UK Biobank GWAS pipeline was developed by B.Elsworth, R.Mitchell, C.Raistrick, L. Paternoster, G.Hemani, T.Gaunt (doi: 10.5523/bris.pnoat8cxo0u52p6ynfaekeigi). The Medical Research Council (MRC) and the University of Bristol support the MRC Integrative Epidemiology Unit [MC_UU_00011/1]. N.M.D. is supported by an Economics and Social Research Council (ESRC) Future Research Leaders grant [ES/N000757/1] and a Norwegian Research Council Grant number 295989. JHB was funded by the Norwegian Research Council with grant number 295989. DME is funded by a National Health and Medical Research Council Senior Research Fellowship (1137714). E.M.T.D. was supported by NIH grants R01AG054628 and R01HD083613, and by the Jacobs Foundation. L.D.H. is supported by a Career Development Award from the UK Medical Research Council (MR/M020894/1). This work is part of a project entitled ‘social and economic consequences of health: causal inference methods and longitudinal, intergenerational data’, which is part of the Health Foundation’s Social and Economic Value of Health Research Programme (Award 807293). The Health Foundation is an independent charity committed to bringing about better health and health care for people in the UK. G.A.V. is supported by a Norwegian Research Council grant code 250335. C.A.R. receives support from the National Institutes of Health (NIH) including R01AG060470, R01AG059329, R01AG058068, R01AG018386, and R01AG046938. NLP receives funding from the National Institutes of Health Grants No. R01AG060470, R01AG059329. The Nord-Trøndelag Health Study (The HUNT Study) is a collaboration between HUNT Research Center (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Nord-Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. The K.G. Jebsen Center for Genetic Epidemiology is funded by Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, NTNU; The Liaison Committee for education, research and innovation in Central Norway; and the Joint Research Committee between St. Olavs Hospital and the Faculty of Medicine and Health Sciences, NTNU. The genotyping in HUNT was financed by the National Institute of Health (NIH); University of Michigan; The Research Council of Norway; The Liaison Committee for education, research and innovation in Central Norway; and the Joint Research Committee between St. Olavs Hospital and the Faculty of Medicine and Health Sciences, NTNU. J.K. has been supported by the Academy of Finland (grants 308248, 312073). R.M.F. and R.N.B. are supported by Sir Henry Dale Fellowship (Wellcome Trust and Royal Society grant: WT104150). G.H. is supported by the Wellcome Trust and Royal Society [208806/ Z/17/Z]. A.H. was funded by the South-Eastern Norway Regional Health Authority, grants 2018059 and 2020022. We thank the customers of 23andMe who answered surveys and participated in this research. No funding body has influenced data collection, analysis or its interpretation. This publication is the work of the authors, who serve as the guarantors for the contents of this paper.
| Funders | Funder number |
|---|---|
| Economics and Social Research Council | ES/N000757/1 |
| Faculty of Medicine and Health Sciences | |
| National Institute of Health | |
| National Institutes of Health | R01AG046938, R01AG060470, R01AG059329, R01AG058068 |
| National Institute on Aging | R01AG018386 |
| University of Michigan | |
| Norges Teknisk-Naturvitenskapelige Universitet | |
| Wellcome Trust | |
| Medical Research Council | MR/M020894/1, 250335 |
| Royal Society | 208806/ Z/17/Z, WT104150 |
| National Health and Medical Research Council | 1137714, R01AG054628, R01HD083613 |
| Academy of Finland | 312073, 308248 |
| Jacobs Foundation | |
| Norges forskningsråd | 295989 |
| Helse Sør-Øst RHF | 2018059, 2020022 |
| St. Olavs Hospital Universitetssykehuset i Trondheim |
Cohort Studies
- Netherlands Twin Register (NTR)
