Educational attainment, health outcomes and mortality: a within-sibship Mendelian randomization study

Laurence J Howe; Humaira Rasheed; Paul R Jones; Dorret I Boomsma; David M Evans; Alexandros Giannelis; Caroline Hayward; John L Hopper; Amanda Hughes; Hannu Lahtinen; Shuai Li; Penelope A Lind; Nicholas G Martin; Pekka Martikainen; Sarah E Medland; Tim T Morris; Michel G Nivard; Jean-Baptiste Pingault; Karri Silventoinen; Jennifer A Smith; Emily A Willoughby; James F Wilson; Within Family Consortium; Bjørn Olav Åsvold; Øyvind E Næss; George Davey Smith; Jaakko Kaprio; Ben Brumpton; Neil M Davies

doi:10.1093/ije/dyad079

Educational attainment, health outcomes and mortality: a within-sibship Mendelian randomization study

Int J Epidemiol. 2023 Oct 5;52(5):1579-1591. doi: 10.1093/ije/dyad079.

Authors

Laurence J Howe^{1

2}, Humaira Rasheed^{1

3

4}, Paul R Jones⁵, Dorret I Boomsma^{6

7}, David M Evans^{1

8

9}, Alexandros Giannelis¹⁰, Caroline Hayward¹¹, John L Hopper¹², Amanda Hughes^{1

2}, Hannu Lahtinen¹³, Shuai Li^{12

14

15}, Penelope A Lind^{16

17

18}, Nicholas G Martin¹⁹, Pekka Martikainen^{13

20

21}, Sarah E Medland^{16

18

22}, Tim T Morris^{1

2}, Michel G Nivard⁶, Jean-Baptiste Pingault^{23

24}, Karri Silventoinen¹³, Jennifer A Smith^{25

26}, Emily A Willoughby¹⁰, James F Wilson^{11

27}; Within Family Consortium; Bjørn Olav Åsvold^{3

28}, Øyvind E Næss^{5

29}, George Davey Smith^{1

2}, Jaakko Kaprio³⁰, Ben Brumpton^{1

3}, Neil M Davies^{1

3

31

32}

Collaborators

Within Family Consortium:
Rafael Ahlskog, Ole A Andreassen, Helga Ask, Archie Campbell, Rosa Cheesman, Yoonsu Cho, Kaare Christensen, Elizabeth C Corfield, Christina C Dahm, Alexandra Havdahl, William D Hill, Shona M Kerr, Antti Latvala, Marianne Nygaard, Teemu Palviainen, Nancy L Pedersen, Robert Plomin, Melissa C Southey, Camilla Stoltenberg

Affiliations

¹ Medical Research Council Integrative Epidemiology Unit, Population Health Sciences, University of Bristol, UK.
² Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
³ K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
⁴ Department of Medicine and Laboratory Sciences, University of Oslo, Oslo, Norway.
⁵ Department of Community Medicine and Global Health, Institute of Health and Society, Faculty of Medicine, University of Oslo, Oslo, Norway.
⁶ Department of Biological Psychology, Netherlands Twin Registry, Vrije Universiteit, Amsterdam, Netherlands.
⁷ Amsterdam Public Health (APH) and Amsterdam Reproduction and Development (AR&D).
⁸ University of Queensland Diamantina Institute, University of Queensland, Brisbane, Australia.
⁹ Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
¹⁰ Department of Psychology, University of Minnesota, Minneapolis, MN, USA.
¹¹ MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK.
¹² Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
¹³ Population Research Unit, University of Helsinki, Helsinki, Finland.
¹⁴ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹⁵ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
¹⁶ Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
¹⁷ School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia.
¹⁸ Faculty of Medicine, University of Queensland, Brisbane, Australia.
¹⁹ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
²⁰ The Max Planck Institute for Demographic Research, Germany.
²¹ Department of Public Health Sciences, Stockholm University, Sweden.
²² School of Psychology, University of Queensland, Brisbane, Australia.
²³ Social Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
²⁴ Department of Clinical, Educational and Health Psychology, University College London, London, UK.
²⁵ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
²⁶ Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
²⁷ Centre for Global Health Research, Usher Institute, University of Edinburgh, Teviot Place, Edinburgh, UK.
²⁸ Department of Endocrinology, Clinic of Medicine, St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
²⁹ Norwegian Institute of Public Health, Oslo, Norway.
³⁰ Institute for Molecular Medicine FIMM, University of Helsinki, Helsinki, Finland.
³¹ Division of Psychiatry, University College London, London, UK.
³² Department of Statistical Sciences, University College London, London, UK.

Abstract

Background: Previous Mendelian randomization (MR) studies using population samples (population MR) have provided evidence for beneficial effects of educational attainment on health outcomes in adulthood. However, estimates from these studies may have been susceptible to bias from population stratification, assortative mating and indirect genetic effects due to unadjusted parental genotypes. MR using genetic association estimates derived from within-sibship models (within-sibship MR) can avoid these potential biases because genetic differences between siblings are due to random segregation at meiosis.

Methods: Applying both population and within-sibship MR, we estimated the effects of genetic liability to educational attainment on body mass index (BMI), cigarette smoking, systolic blood pressure (SBP) and all-cause mortality. MR analyses used individual-level data on 72 932 siblings from UK Biobank and the Norwegian HUNT study, and summary-level data from a within-sibship Genome-wide Association Study including >140 000 individuals.

Results: Both population and within-sibship MR estimates provided evidence that educational attainment decreased BMI, cigarette smoking and SBP. Genetic variant-outcome associations attenuated in the within-sibship model, but genetic variant-educational attainment associations also attenuated to a similar extent. Thus, within-sibship and population MR estimates were largely consistent. The within-sibship MR estimate of education on mortality was imprecise but consistent with a putative effect.

Conclusions: These results provide evidence of beneficial individual-level effects of education (or liability to education) on adulthood health, independently of potential demographic and family-level confounders.

Keywords: Mendelian randomization; Within-sibship; educational attainment; mortality.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Academic Success*
Educational Status
Genome-Wide Association Study
Humans
Mendelian Randomization Analysis* / methods
Outcome Assessment, Health Care
Polymorphism, Single Nucleotide

Abstract

Publication types

MeSH terms

Grants and funding