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Genetics as a research tool: A natural experiment to elucidate the causal effects of social mobility on health.

Projectomschrijving

Doel

Waarom hebben mensen met een lagere sociaal economische status (SES) vaker mentale en fysieke gezondheidsproblemen en geldt dit ook voor hun kinderen? Dit onderzoek bekeek in hoeverre deze gezondheidsproblemen in causaal verband konden worden gebracht met onderwijsparticipatie. Ook werd onderzocht in hoeverre onderwijs de gezondheidsachterstand mogelijk gelijk zou kunnen trekken. 

Onderzoek

Hiervoor werd gebruik gemaakt van twee ‘natuurlijke’ experimenten: discordante tweelingen en Mendelian Randomization (MR). In het eerste onderzoek werd gekeken naar genetisch identieke tweelingen die verschillen in SES. In het tweede onderzoek werd gebruik gemaakt van het feit dat welke genen iemand van zijn ouders erft gebaseerd is op toeval.

Resultaten

Het onderzoek laat zien dat er waarschijnlijk een causaal effect is van succes op school op depressie, PTSD, angst en sommige andere psychiatrische aandoeningen bij volwassenen. Het lijkt aannemelijk dat als er een causaal effect is van de duur van onderwijs op mentale gezondheid, inkomen een mediator van dit effect is. 

Ook laat de studie effecten zien van onderwijs op bijvoorbeeld BMI, roken en bloeddruk. Deze effecten zijn aantoonbaar in de verschillende studies, maar het is belangrijk te benadrukkend dat oorzakelijke analyse een kleinere relatie tussen scholing en BMI laat zien dan observationeel werk. Dit betekent dat er naast het onderwijs zelf nog meer verschillen in kansen, omgeving en gezin kunnen zijn die zorgen dat er SES verschillen in gezondheidsuitkomsten zijn.

Producten

Titel: The Relationship of Attention-deficit/Hyperactivity Disorder with Post-traumatic Stress Disorder: A Two-Sample Mendelian Randomization and Population-Based Sibling Comparison Study.
Auteur: Frank R. Wendt, PhD, Miguel Garcia-Argibay, PhD, Brenda Cabrera-Mendoza, MD, PhD, Unnur A. Valdimarsdóttir, PhD, Joel Gelernter, MD, Murray B. Stein, MD, MPH, Michel G. Nivard, PhD, Adam X. Maihofer, PhD, Post-Traumatic Stress Disorder Working Group of the Psychiatric Genomics Consortium, Caroline M. Nievergelt, PhD, Henrik Larsson, PhD, Manuel Mattheisen, MD, Renato Polimanti, PhD, Sandra Meier, PhD
Magazine: Biological Psychiatry
Link: https://doi.org/10.1016/j.biopsych.2022.08.012
Titel: Genomic structural equation modelling provides insights into the multivariate genetic architecture of complex traits
Auteur: Grotzinger, Andrew D., Rhemtulla, Mijke, de Vlaming, Ronald, Ritchie, Stuart J., Mallard, Travis T., Hill, W. David, Ip, Hill F., Marioni, Riccardo E., McIntosh, Andrew M., Deary, Ian J., Koellinger, Philipp D., Harden, K. Paige, Nivard, Michel G., Tucker-Drob, Elliot M.
Magazine: Nature
Titel: Intergenerational transmission of education and ADHD: Effects of parental genotypes
Auteur: de Zeeuw, Eveline L., Hottenga, Jouke-Jan, Ouwens, Klaasjan G., Dolan, Conor V., Ehli, Erik A., Davies, Gareth E., Boomsma, Dorret I., van Bergen, Elsje
Magazine: BioRxiv
Titel: Literacy skills seem to fuel literacy enjoyment, rather than vice versa
Auteur: Elsje van Bergen, Sara A. Hart, Antti Latvala, Eero Vuoksimaa, Asko Tolvanen, Minna Torppa
Magazine: Developmental Science
Link: http://10.1111/desc.13325
Titel: Ultra-rare and common genetic variant analysis converge to implicate negative selection and neuronal processes in the aetiology of schizophrenia
Auteur: Wonuola A. Akingbuwa, Anke R. Hammerschlag, Meike Bartels, Michel G. Nivard & Christel M. Middeldorp
Magazine: Molecular Psychiatry
Link: https://doi.org/10.1038/s41380-022-01621-8
Titel: Genetic Consequences of Social Stratification in Great Britain
Auteur: Abdellaoui, Abdel, Hugh-Jones, David, Kemper, Kathryn E., Holtz, Yan, Nivard, Michel G., Veul, Laura, Yengo, Loic, Zietsch, Brendan P., Frayling, Timothy M., Wray, Naomi, Yang, Jian, Verweij, Karin J.H., Visscher, Peter M.
Magazine: BioRxiv
Titel: Intergenerational transmission of body mass index and associations with educational attainment
Auteur: Hekmat Alrouh, Elsje van Bergen, Eveline de Zeeuw, Conor Dolan & Dorret I. Boomsma
Magazine: BMC Public Health
Link: https://doi.org/10.1186/s12889-022-13270-1
Titel: Estimating effects of parents’ cognitive and non-cognitive skills on offspring education using polygenic scores
Auteur: Perline A. Demange, Jouke Jan Hottenga, Abdel Abdellaoui, Espen Moen Eilertsen, Margherita Malanchini, Benjamin W. Domingue, Emma Armstrong-Carter, Eveline L. de Zeeuw, Kaili Rimfeld, Dorret I. Boomsma, Elsje van Bergen, Gerome Breen, Michel G. Nivard & Rosa Cheesman
Magazine: NATURE COMMUNICATIONS
Link: https://www.nature.com/articles/s41467-022-32003-x
Titel: Safe Linkage of Cohort and Population-Based Register Data in a Genomewide Association Study on Health Care Expenditure
Auteur: Eveline L. de Zeeuw , Lykle Voort , Ruurd Schoonhoven , Michel G. Nivard , Thomas Emery , Jouke-Jan Hottenga , Gonneke A. H. M. Willemsen , Pearl A. Dykstra , Narges Zarrabi , John D. Kartopawiro and Dorret I. Boomsma
Magazine: Twin Research and Human Genetics
Link: http://10.1017/thg.2021.18
Titel: A Genetic Investigation of the Well-Being Spectrum
Auteur: Baselmans, B. M. L., van de Weijer, M. P., Abdellaoui, A., Vink, J. M., Hottenga, J. J., Willemsen, G., Nivard, M. G., de Geus, E. J. C., Boomsma, D. I., Bartels, M.
Magazine: Nature Genetics
Titel: Item-level genome-wide association study of the alcohol use disorders identification test in three population-based cohorts
Auteur: Travis T. Mallard, M.A., Jeanne E. Savage, Ph.D., Emma C. Johnson, Ph.D., Yuye Huang, Alexis C. Edwards, Ph.D., Jouke J. Hottenga, Ph.D., Andrew D. Grotzinger, M.A., Daniel E. Gustavson, Ph.D., Mariela V. Jennings, B.Sc., Andrey Anokhin, Ph.D., Danielle M. Dick, Ph.D., Howard J. Edenberg, Ph.D., John R. Kramer, Ph.D., Dongbing Lai, Ph.D., Jacquelyn L. Meyers, Ph.D., Ashwini K. Pandey, Ph.D., Kathryn Paige Harden, Ph.D., Michel G. Nivard, Ph.D., Eco J.C. de Geus, Ph.D., Dorret I. Boomsma, Ph.D.,
Magazine: American Journal of Psychiatry
Link: http://10.1176/appi.ajp.2020.20091390
Titel: Developmental co-occurrence of psychopathology dimensions in childhood
Auteur: Andrea G. Allegrini, Toos van Beijsterveldt, Dorret I. Boomsma, Kaili Rimfeld, Jean-Baptiste Pingault, Robert Plomin, Meike Bartels,Michel G. Nivard
Magazine: Journal of Child Psychology and Psychiatry
Link: https://doi.org/10.1002/jcv2.12100
Titel: Genetic correlates of socio-economic status influence the pattern of shared heritability across mental health traits
Auteur: Andries T. Marees, Dirk J. A. Smit, Abdel Abdellaoui, Michel G. Nivard, Wim van den Brink, Damiaan Denys, Titus J. Galama, Karin J. H. Verweij & Eske M. Derks
Magazine: Nature Human Behaviou
Link: http://10.1038/s41562-021-01053-4
Titel: Investigating the genetic architecture of noncognitive skills using GWAS-by-subtraction
Auteur: Perline A. Demange, Margherita Malanchini, Travis T. Mallard, Pietro Biroli, Simon R. Cox, Andrew D. Grotzinger, Elliot M. Tucker-Drob, Abdel Abdellaoui, Louise Arseneault, Elsje van Bergen, Dorret I. Boomsma, Avshalom Caspi, David L. Corcoran, Benjamin W. Domingue, Kathleen Mullan Harris, Hill F. Ip, Colter Mitchell, Terrie E. Moffitt, Richie Poulton, Joseph A. Prinz, Karen Sugden, Jasmin Wertz, Benjamin S. Williams, Eveline L. de Zeeuw, Daniel W. Belsky, K. Paige Harden & Michel G. Nivard
Magazine: Nature Genetics
Link: https://www.nature.com/articles/s41588-020-00754-2
Titel: Genetic Associations Between Childhood Psychopathology and Adult Depression and Associated Traits in 42?998 Individuals
Auteur: Wonuola A. Akingbuwa, MSc; Anke R. Hammerschlag, PhD; Eshim S. Jami, MSc; Andrea G. Allegrini, MSc; Ville Karhunen, MSc; Hannah Sallis, PhD; Helga Ask, PhD; Ragna B. Askeland, MSc; Bart Baselmans, PhD; Elizabeth Diemer, ScM; Fiona A. Hagenbeek, MSc; Alexandra Havdahl, PhD; Jouke-Jan Hottenga, PhD; Hamdi Mbarek, PhD; Fernando Rivadeneira, PhD; Martin Tesli, PhD; Catharina van Beijsterveldt, PhD; Gerome Breen, PhD; Cathryn M. Lewis, PhD; Anita Thapar, PhD; Dorret I. Boomsma, PhD; Ralf Kuja-Halkol
Magazine: JAMA Psychiatry
Link: http://10.1001/jamapsychiatry.2020.0527
Titel: Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects
Auteur: Laurence J. Howe, Michel G. Nivard, Tim T. Morris, Ailin F. Hansen, Humaira Rasheed, Yoonsu Cho, Geetha Chittoor, Rafael Ahlskog, Penelope A. Lind, Teemu Palviainen, Matthijs D. van der Zee, Rosa Cheesman, Massimo Mangino, Yunzhang Wang, Shuai Li, Lucija Klaric, Scott M. Ratliff, Lawrence F. Bielak, Marianne Nygaard, Alexandros Giannelis, Emily A. Willoughby, Chandra A. Reynolds, Jared V. Balbona, Ole A. Andreassen, Helga Ask, Aris Baras, Christopher R. Bauer, Dorret I. Boomsma, Archie Campbell,
Magazine: Nature Genetics
Link: https://doi.org/10.1038/s41588-022-01062-7
Titel: Gene–environment correlations across geographic regions affect genome-wide association studies
Auteur: Abdel Abdellaoui, Conor V. Dolan, Karin J. H. Verweij & Michel G. Nivard
Magazine: Nature Genetics
Link: https://www.nature.com/articles/s41588-022-01158-0
Titel: Genetic architecture of 11 major psychiatric disorders at biobehavioral, functional genomic and molecular genetic levels of analysis
Auteur: Andrew D. Grotzinger, Travis T. Mallard, Wonuola A. Akingbuwa, Hill F. Ip, Mark J. Adams, Cathryn M. Lewis, Andrew M. McIntosh, Jakob Grove, Søren Dalsgaard, Klaus-Peter Lesch, Nora Strom, Sandra M. Meier, Manuel Mattheisen, Anders D. Børglum, Ole Mors, Gerome Breen, iPSYCH, Tourette Syndrome and Obsessive Compulsive Disorder Working Group of the Psychiatric Genetics Consortium, Bipolar Disorder Working Group of the Psychiatric Genetics Consortium, Major Depressive Disorder Working Group of th
Magazine: Nature Genetics
Link: https://doi.org/10.1038/s41588-022-01057-4
Titel: Nurture might be nature: Cautionary tales and proposed solutions
Auteur: Sara A. Hart, Callie Little & Elsje van Bergen
Magazine: npj schizophrenia
Link: http://10.1038/s41539-020-00079-z
Titel: Estimating direct and indirect genetic effects on offspring phenotypes using genome-wide summary results data
Auteur: Nicole M. Warrington, Liang-Dar Hwang, Michel G. Nivard & David M. Evans
Magazine: Nature Communications
Link: https://doi.org/10.1038/s41467-021-25723-z
Titel: Genetic associations with non-cognitive factors of educational attainment
Auteur: Demange P., Malanchini M., Maillard T., Grotzinger A., Ip H., Wertz J., Freis S., Domingue B., Mitchell C., de Zeeuw E., van Bergen E., Boomsma D., Biroli P., Tucker-Drob E., Belsky D., Harden P., Nivard M.

Verslagen


Samenvatting van de aanvraag

Parents of lower socioeconomic status (SES) not only tend to have more health problems, but also tend to have offspring with more health problems. What remains a question is whether this association reflects a causal effect of SES on health, or reflects genetic or environmental confounding. Causality is typically studied by randomized controlled trials, where confounds are random over conditions and easily controlled for. However, it is not feasible to randomly allocate people to intervention conditions in which SES is altered, so to study causal influences of SES on health we rely on natural experiments. We propose to apply two natural experiments to study intergenerational causality. In these studies genetics serves as a research tool. Using this tool we will study effects of different SES indicators (e.g. educational attainment (EA), household income, and social deprivation) on physical and mental health outcomes. In the first design, referred to as the twin discordance design, we will study genetically-identical (i.e., monozygotic or MZ) twins who differ in (so are discordant for) the SES indicator. Does the twin member who is of lower SES compared to his/her co-twin also suffer poorer health? If so, this strengthens the evidence for a causal relation between SES and health, because the association is controlled for genetic and childhood confounders, as these are identical in MZ twins. In the second design, the intergenerational (Mendelian randomization, or MR) design, we study the effects of parental and offspring SES on offspring health outcomes. We leverage the fact that each offspring within a nuclear family inherits a mixture of genetic variants from both parents, in some cases inheriting more SES increasing (vs. decreasing) genetic variants, rendering his or her genetic predisposition for SES above (vs. below) that of his/her parents. As genotypes which predispose to higher or lower SES are inherited randomly, they form the perfect basis for natural experiments. The genetic predispositions are utilized as instruments to identify the ’true’ effect of SES on health. This intergenerational design enables us to study the effect of both parental and offspring SES on health. At the etiological level, individual differences in SES can be explained by the interplay of genetic and environmental differences. Consider for example EA, important influences on EA are IQ and personality, which in turn are influenced by genes and environmental factors. Hence, the complex multifactorial construct of SES is also influenced, but not determined, by genes. That is, differences among people in SES are partly due to genetic differences, like a genetic predisposition to ease-of-learning and perseverance. The twin discordance and intergenerational MR design will be employed to test causal effects of aspects of SES on health, in particular cardio-metabolic (e.g., myocardial infarction and type II diabetes) and mental health (e.g., depression and ADHD). These outcomes are prevalent and impose a heavy burden on affected individuals, families, and society at large. As it also conceivable that health problems lead to lower SES, we test for the presence of causality in either direction. To realize this project we will combine three rich and unique research facilities: the Netherlands Twin Register (NTR), Statistics Netherlands (CBS), and the Geoscience and Health Cohort Consortium (GECCO). NTR includes thousands of twin families with longitudinal health and genetic data and very good national coverage (see: Figure 1 Together these resources provide wide variety of SES indicators, which, if added to the models separately, can shed light on the mechanism(s) of how SES influences health. In addition, CBS (diagnosis and hospital data) and NTR (questionnaire and self-report) provide a wealth of health outcome data. Replication of findings will be performed in international twin registers with access to similar data. The project can implicate and address the causality of the association between SES and health outcomes. Malleable behaviors and exposures that are causally implicated provide evidence-based targets for future interventions to improve health outcomes. Behaviors and exposures that are associated with mental or cardio-metabolic health, but not because of causal mechanisms, can be discarded as intervention targets, saving valuable time and resources. Consider, for example, the finding that a failure to complete secondary education causally predisposes poor health outcomes, but only in those with a lower parental SES. The ability to easily identify those at risk for poor health outcomes, allows for the selective application of preventative programs (e.g. adult education), and risk screening (e.g. population screening for certain disease at earlier ages dependent on educational background). Thus, findings will improve health-economic modeling of the consequences of social inequality, and thus shape effective policy.

Kenmerken

Projectnummer:
531003014
Looptijd: 100%
Looptijd: 100 %
2018
2023
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
prof. dr. D.I. Boomsma
Verantwoordelijke organisatie:
Vrije Universiteit Amsterdam
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Kennisbundel gezonde wijk

In de kennisbundel Gezond leven in gemeente en regio vindt u een selectie van de meest bruikbare kennis uit onderzoek naar gezondheidsaanpakken in de wijk voor gemeenten en GGD’en. In ruim 4 jaar is de kennis opgedaan in 35 projecten, met subsidie uit ons Preventieprogramma.