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

Laurence J. Howe; Humaira Rasheed; Dorret I. Boomsma; Michel G. Nivard; Jaakko Kaprio; Ben Brumpton; Neil M. Davies; Within Family Consortium

doi:10.1093/ije/dyad079

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

Laurence J. Howe^*, Humaira Rasheed, Dorret I. Boomsma, Michel G. Nivard, Jaakko Kaprio, Ben Brumpton, Neil M. Davies, Within Family Consortium

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

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 72932 siblings from UK Biobank and the Norwegian HUNT study, and summary-level data from a within-sibship Genome-wide Association Study including >140000 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.

Original language	English
Pages (from-to)	1579-1591
Number of pages	13
Journal	International Journal of Epidemiology
Volume	52
Issue number	5
Early online date	9 Jun 2023
DOIs	https://doi.org/10.1093/ije/dyad079
Publication status	Published - Oct 2023

Bibliographical note

Funding Information:
The University of Bristol support the MRC Integrative Epidemiology Unit (MC_UU_00011/1). The Trøndelag Health Study (HUNT) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority and the Norwegian Institute of Public Health. The genotyping in HUNT was financed by the National Institutes of Health; 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. The K.G. Jebsen Center for Genetic Epidemiology is financed by Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, NTNU, Norway. N.M.D. is supported by a Norwegian Research Council Grant number 295989. J.F.W. acknowledges support from the MRC Human Genetics Unit programme grant, ‘Quantitative traits in health and disease’ (U. MC_UU_00007/10). J.B.P. is funded by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 863981). S.L. is a Victorian Cancer Agency Early Career Research Fellow (ECRF19020). J.L.H. is a National Health and Medical Research Council Senior Principal Research Fellow. P.R.J. and O.E.N. are funded by the Research Council of Norway (#28743). J.K. is funded by the Academy of Finland (grants 312073 and 336823) and the Sigrid Juselius Foundation. P.M. was supported by the Academy of Finland (#308247, # 345219) and the ERC under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 101019329). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. This publication is the work of the authors, who serve as the guarantors for the contents of this paper. Acknowledgements

Publisher Copyright:
© 2023 The Author(s). Published by Oxford University Press on behalf of the International Epidemiological Association.

Funding

The University of Bristol support the MRC Integrative Epidemiology Unit (MC_UU_00011/1). The Trøndelag Health Study (HUNT) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority and the Norwegian Institute of Public Health. The genotyping in HUNT was financed by the National Institutes of Health; 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. The K.G. Jebsen Center for Genetic Epidemiology is financed by Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, NTNU, Norway. N.M.D. is supported by a Norwegian Research Council Grant number 295989. J.F.W. acknowledges support from the MRC Human Genetics Unit programme grant, ‘Quantitative traits in health and disease’ (U. MC_UU_00007/10). J.B.P. is funded by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 863981). S.L. is a Victorian Cancer Agency Early Career Research Fellow (ECRF19020). J.L.H. is a National Health and Medical Research Council Senior Principal Research Fellow. P.R.J. and O.E.N. are funded by the Research Council of Norway (#28743). J.K. is funded by the Academy of Finland (grants 312073 and 336823) and the Sigrid Juselius Foundation. P.M. was supported by the Academy of Finland (#308247, # 345219) and the ERC under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 101019329). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. This publication is the work of the authors, who serve as the guarantors for the contents of this paper. Acknowledgements

Funders	Funder number
Liaison Committee for education, research and innovation in Central Norway
National Institutes of Health
University of Michigan
Norges Teknisk-Naturvitenskapelige Universitet
Horizon 2020 Framework Programme	28743, 863981
Horizon 2020 Framework Programme
Faculté de médecine et des sciences de la santé, Université de Sherbrooke
Medical Research Council	MC_UU_00007/10
Medical Research Council
European Research Council
Academy of Finland	312073, 336823
Academy of Finland
Norges forskningsråd	295989
Norges forskningsråd
Sigrid Juséliuksen Säätiö	345219, 101019329, 308247
Sigrid Juséliuksen Säätiö
St. Olavs Hospital Universitetssykehuset i Trondheim

Keywords

educational attainment
Mendelian randomization
mortality
Within-sibship

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@article{5fe73600caca47a8ab68538779d75145,

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

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 72932 siblings from UK Biobank and the Norwegian HUNT study, and summary-level data from a within-sibship Genome-wide Association Study including >140000 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 = "educational attainment, Mendelian randomization, mortality, Within-sibship",

author = "Howe, {Laurence J.} and Humaira Rasheed and Jones, {Paul R.} and Boomsma, {Dorret I.} and Evans, {David M.} and Alexandros Giannelis and Caroline Hayward and Hopper, {John L.} and Amanda Hughes and Hannu Lahtinen and Shuai Li and Lind, {Penelope A.} and Martin, {Nicholas G.} and Pekka Martikainen and Medland, {Sarah E.} and Morris, {Tim T.} and Nivard, {Michel G.} and Pingault, {Jean Baptiste} and Karri Silventoinen and Smith, {Jennifer A.} and Willoughby, {Emily A.} and Wilson, {James F.} and {\AA}svold, {Bj{\o}rn Olav} and Rafael Ahlskog and Andreassen, {Ole A.} and Helga Ask and Archie Campbell and Rosa Cheesman and Yoonsu Cho and Kaare Christensen and Corfield, {Elizabeth C.} and Dahm, {Christina C.} and Alexandra Havdahl and Hill, {William D.} and Kerr, {Shona M.} and Antti Latvala and Marianne Nygaard and Teemu Palviainen and Pedersen, {Nancy L.} and Robert Plomin and Southey, {Melissa C.} and Camilla Stoltenberg and {\AA}svold, {Bj{\o}rn Olav} and N{\ae}ss, {{\O}yvind E.} and {Davey Smith}, George and Jaakko Kaprio and Ben Brumpton and Davies, {Neil M.} and {Within Family Consortium}",

note = "Funding Information: The University of Bristol support the MRC Integrative Epidemiology Unit (MC_UU_00011/1). The Tr{\o}ndelag Health Study (HUNT) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Tr{\o}ndelag County Council, Central Norway Regional Health Authority and the Norwegian Institute of Public Health. The genotyping in HUNT was financed by the National Institutes of Health; 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. The K.G. Jebsen Center for Genetic Epidemiology is financed by Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, NTNU, Norway. N.M.D. is supported by a Norwegian Research Council Grant number 295989. J.F.W. acknowledges support from the MRC Human Genetics Unit programme grant, {\textquoteleft}Quantitative traits in health and disease{\textquoteright} (U. MC_UU_00007/10). J.B.P. is funded by the European Research Council (ERC) under the European Union{\textquoteright}s Horizon 2020 research and innovation programme (grant agreement No. 863981). S.L. is a Victorian Cancer Agency Early Career Research Fellow (ECRF19020). J.L.H. is a National Health and Medical Research Council Senior Principal Research Fellow. P.R.J. and O.E.N. are funded by the Research Council of Norway (#28743). J.K. is funded by the Academy of Finland (grants 312073 and 336823) and the Sigrid Juselius Foundation. P.M. was supported by the Academy of Finland (#308247, # 345219) and the ERC under the European Union{\textquoteright}s Horizon 2020 research and innovation programme (grant agreement No. 101019329). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. This publication is the work of the authors, who serve as the guarantors for the contents of this paper. Acknowledgements Publisher Copyright: {\textcopyright} 2023 The Author(s). Published by Oxford University Press on behalf of the International Epidemiological Association.",

year = "2023",

month = oct,

doi = "10.1093/ije/dyad079",

language = "English",

volume = "52",

pages = "1579--1591",

journal = "International Journal of Epidemiology",

issn = "0300-5771",

publisher = "Oxford University Press",

number = "5",

}

TY - JOUR

T1 - Educational attainment, health outcomes and mortality

T2 - a within-sibship Mendelian randomization study

AU - Howe, Laurence J.

AU - Rasheed, Humaira

AU - Jones, Paul R.

AU - Boomsma, Dorret I.

AU - Evans, David M.

AU - Giannelis, Alexandros

AU - Hayward, Caroline

AU - Hopper, John L.

AU - Hughes, Amanda

AU - Lahtinen, Hannu

AU - Li, Shuai

AU - Lind, Penelope A.

AU - Martin, Nicholas G.

AU - Martikainen, Pekka

AU - Medland, Sarah E.

AU - Morris, Tim T.

AU - Nivard, Michel G.

AU - Pingault, Jean Baptiste

AU - Silventoinen, Karri

AU - Smith, Jennifer A.

AU - Willoughby, Emily A.

AU - Wilson, James F.

AU - Åsvold, Bjørn Olav

AU - Ahlskog, Rafael

AU - Andreassen, Ole A.

AU - Ask, Helga

AU - Campbell, Archie

AU - Cheesman, Rosa

AU - Cho, Yoonsu

AU - Christensen, Kaare

AU - Corfield, Elizabeth C.

AU - Dahm, Christina C.

AU - Havdahl, Alexandra

AU - Hill, William D.

AU - Kerr, Shona M.

AU - Latvala, Antti

AU - Nygaard, Marianne

AU - Palviainen, Teemu

AU - Pedersen, Nancy L.

AU - Plomin, Robert

AU - Southey, Melissa C.

AU - Stoltenberg, Camilla

AU - Åsvold, Bjørn Olav

AU - Næss, Øyvind E.

AU - Davey Smith, George

AU - Kaprio, Jaakko

AU - Brumpton, Ben

AU - Davies, Neil M.

AU - Within Family Consortium

N1 - Funding Information: The University of Bristol support the MRC Integrative Epidemiology Unit (MC_UU_00011/1). The Trøndelag Health Study (HUNT) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority and the Norwegian Institute of Public Health. The genotyping in HUNT was financed by the National Institutes of Health; 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. The K.G. Jebsen Center for Genetic Epidemiology is financed by Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, NTNU, Norway. N.M.D. is supported by a Norwegian Research Council Grant number 295989. J.F.W. acknowledges support from the MRC Human Genetics Unit programme grant, ‘Quantitative traits in health and disease’ (U. MC_UU_00007/10). J.B.P. is funded by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 863981). S.L. is a Victorian Cancer Agency Early Career Research Fellow (ECRF19020). J.L.H. is a National Health and Medical Research Council Senior Principal Research Fellow. P.R.J. and O.E.N. are funded by the Research Council of Norway (#28743). J.K. is funded by the Academy of Finland (grants 312073 and 336823) and the Sigrid Juselius Foundation. P.M. was supported by the Academy of Finland (#308247, # 345219) and the ERC under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 101019329). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. This publication is the work of the authors, who serve as the guarantors for the contents of this paper. Acknowledgements Publisher Copyright: © 2023 The Author(s). Published by Oxford University Press on behalf of the International Epidemiological Association.

PY - 2023/10

Y1 - 2023/10

N2 - 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 72932 siblings from UK Biobank and the Norwegian HUNT study, and summary-level data from a within-sibship Genome-wide Association Study including >140000 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.

AB - 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 72932 siblings from UK Biobank and the Norwegian HUNT study, and summary-level data from a within-sibship Genome-wide Association Study including >140000 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.

KW - educational attainment

KW - Mendelian randomization

KW - mortality

KW - Within-sibship

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UR - http://www.scopus.com/inward/citedby.url?scp=85173847739&partnerID=8YFLogxK

U2 - 10.1093/ije/dyad079

DO - 10.1093/ije/dyad079

M3 - Article

C2 - 37295953

SN - 0300-5771

VL - 52

SP - 1579

EP - 1591

JO - International Journal of Epidemiology

JF - International Journal of Epidemiology

IS - 5

ER -

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

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