CoChat
Sign Up
Cited by 74Genetic Associations and EpidemiologyAssisted Reproductive Technology and Twin PregnancyAdvanced Causal Inference Techniques

Twins and Causal Inference: Leveraging Nature's Experiment

Open access
McAdams, Tom A., Rijsdijk, Fruhling V., Zavos, Helena M.S., Pingault, Jean-Baptiste·2021·Cold Spring Harbor Perspectives in Medicine
DOI 10.1101/cshperspect.a039552PMC PMC8168524
Open this paper in CoChat — free accountOpen PDF

Abstract

In this review, we discuss how samples comprising monozygotic and dizygotic twin pairs can be used for the purpose of strengthening causal inference by controlling for shared influences on exposure and outcome. We begin by briefly introducing how twin data can be used to inform the biometric decomposition of population variance into genetic, shared environmental, and nonshared environmental influences. We then discuss how extensions to this model can be used to explore whether associations between exposure and outcome survive correction for shared etiology (common causes). We review several analytical approaches that can be applied to twin data for this purpose. These include multivariate structural equation models, cotwin control methods, direction of causation models (cross-sectional and longitudinal), and extended family designs used to assess intergenerational associations. We conclude by highlighting some of the limitations and considerations that researchers should be aware of when using twin data for the purposes of interrogating causal hypotheses.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1101/cshperspect.a039552

Cites

10 of 10 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 66

  1. Ahmadzadeh YI, Eley TC, Hannigan LJ, Creswell C, Lich- tenstein P, Reiss D, Spotts E, Ganigan J, Neiderhiser JM, Rijsdijk FV, et al. 2020. Parental criticism and adolescent internalising symptoms: associations remain after ac- counting for shared genetic effects. medRxiv doi:10 .1101/2020.05.07.20084319 · DOI
  2. Ball HA, Sumathipala A, Siribaddana SH, Kovas Y, Glozier N, McGuffin P, Hotopf M. 2009. Genetic and environ- mental contributions to depression in Sri Lanka. Br J Psychiatry 195: 504-509. doi:10.1192/bjp.bp.109.063529 · DOI
  3. Carlin JB, Gurrin LC, Sterne JA, Morley R, Dwyer T. 2005. Regression models for twin studies: a critical review. Int J Epidemiol 34: 1089-1099. doi:10.1093/ije/dyi153 · DOI
  4. Carr AB, Einstein R, Lai LY, Martin NG, Starmer GA. 1981. Vitamin C and the common cold using identical twins as controls. Med J Aust 2: 411-412. doi:10.5694/j.1326-5377 .1981.tb101032.x · DOI
  5. Cecil CA, Barker ED, Jaffee SR, Viding E. 2012. Association between maladaptive parenting and child self-control over time: cross-lagged study using a monozygotic twin difference design. Br J Psychiatry 201: 291-297. doi:10 .1192/bjp.bp.111.107581 · DOI
  6. Cheesman R, Eilertsen EM, Ahmadzadeh YI, Gjerde LC, Hannigan LJ, Havdahl A, Young AI, Eley TC, Rasmus Njolstad P, Magnus PM, et al. 2020. How important are parents in the development of child anxiety and depres- sion? A genomic analysis of parent-offspring trios in the Norwegian Mother, Father and Child Cohort Study (MoBa). medRxiv doi:10.1101/2020.04.14.20064782 · DOI
  7. Conley D, Rauscher E, Dawes C, Magnusson PK, Siegal ML. 2013. Heritability and the equal environments assump- tion: evidence from multiple samples of misclassified twins. Behav Genet 43: 415-426. doi:10.1007/s10519- 013-9602-1 · DOI
  8. Davey Smith G, Hemani G. 2014. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet 23: R89-R98. doi:10.1093/ hmg/ddu328 D'Onofrio BM, Turkheimer EN, Eaves LJ, Corey LA, Berg K, Solaas MH, Emery RE. 2003. The role of the children of twins design in elucidating causal relations between par- ent characteristics and child outcomes. J Child Psychol Psychiatry Allied Disciplines 44: 1130-1144. doi:10 .1111/1469-7610.00196 · DOI
  9. Duffy DL, Martin NG. 1994. Inferring the direction of cau- sation in cross-sectional twin data-theoretical and em- pirical considerations. Genet Epidemiol 11: 483-502. doi:10.1002/gepi.1370110606 · DOI
  10. Eaves LJ, Pourcain BS, Smith GD, York TP, Evans DM. 2014. Resolving the effects of maternal and offspring genotype on dyadic outcomes in genome wide complex trait anal- ysis ("M-GCTA"). Behav Genet 44: 445-455. doi:10.1007/ s10519-014-9666-6 · DOI
  11. Fletcher JM. 2011. The promise and pitfalls of combining genetic and economic research. Health Econ 20: 889-892. doi:10.1002/hec.1745 · DOI
  12. Fletcher JM, Lehrer SF. 2011. Genetic lotteries within fam- ilies. J Health Econ 30: 647-659. doi:10.1016/j.jhealeco .2011.04.005 · DOI
  13. Everitt BS, Howell DC), Vol. 1, pp. 496-499. Wiley, Ho- boken, NJ.
  14. Gillespie NA, Gehrman P, Byrne EM, Kendler KS, Heath AC, Martin NG. 2012. Modeling the direction of causa- tion between cross-sectional measures of disrupted sleep, anxiety and depression in a sample of male and female Australian twins. J Sleep Res 21: 675-683. doi:10.1111/j .1365-2869.2012.01026.x · DOI
  15. Gjerde LC, Eilertsen EM, Hannigan LJ, Eley T, Røysamb E, Reichborn-Kjennerud T, Rijsdijk FV, McAdams TA, Ystrom E. 2019. Associations between maternal depres- sive symptoms and risk for offspring early-life psychopa- thology: the role of genetic and non-genetic mechanisms. Psychol Med 1-9. doi:10.1017/S0033291719003301 · DOI · Paper page
  16. Hannigan LJ, Eilertsen EM, Gjerde LC, Reichborn-Kjen- nerud T, Eley TC, Rijsdijk FV, Ystrom E, McAdams TA. 2018. Maternal prenatal depressive symptoms and risk for early-life psychopathology in offspring: genetic analyses in the Norwegian Mother and Child Birth Cohort Study. Lancet Psychiatry 5: 808-815. doi:10.1016/S2215-0366 (18)30225-6 · DOI
  17. Haworth CM, Wright MJ, Luciano M, Martin NG, de Geus EJ, van Beijsterveldt CEM, Bartels M, Posthuma D, Boomsma DI, Davis OSP, et al. 2010. The heritability of general cognitive ability increases linearly from childhood to young adulthood. Mol Psychiatry 15: 1112-1120. doi:10.1038/mp.2009.55 · DOI
  18. Haworth CM, Nelson SK, Layous K, Carter K, Bao KJ, Lyu- bomirsky S, Plomin R. 2016. Stability and change in ge- netic and environmental influences on well-being in re- sponse to an intervention. PLoS ONE 11: e0155538. doi:10.1371/journal.pone.0155538 · DOI
  19. Heath AC, Kendler KS, Eaves LJ, Markell D. 1985. The res- olution of cultural and biological inheritance: informa- tiveness of different relationships. Behav Genet 15: 439- 465. doi:10.1007/BF01066238 · DOI
  20. Heath AC, Kessler RC, Neale MC, Hewitt JK, Eaves LJ, Ken- dler KS. 1993. Testing hypotheses about direction of cau- sation using cross-sectional family data. Behav Genet 23: 29-50. doi:10.1007/BF01067552 · DOI
  21. Hjelmborg J, Korhonen T, Holst K, Skytthe A, Pukkala E, Kutschke J, Harris JR, Mucci LA, Christensen K, Czene K, et al. 2017. Lung cancer, genetic predisposition and smok- ing: the Nordic Twin Study of Cancer. Thorax 72: 1021- 1027. doi:10.1136/thoraxjnl-2015-207921 · DOI
  22. Hur YM. 2008. Sex differences in genetic and environmental contributions to depression symptoms in South Korean adolescent and young adult twins. Twin Res Hum Genet 11: 306-313. doi:10.1375/twin.11.3.306 · DOI
  23. Hur YM, Bogl LH, Ordoñana JR, Taylor J, Hart SA, Tuvblad C, Ystrom E, Dalgård C, Skytthe A, Willemsen G. 2020. Twin family registries worldwide: an important resource for scientific research. Twin Res Hum Genet 22: 427-437. doi:10.1017/thg.2019.121 · DOI
  24. Ã Hwang L-D, Davies NM, Warrington NM, Evans DM. 2020. Integrating family-based and Mendelian randomization designs. Cold Spring Harb Perspect Med doi:10.1101/ cshperspect.a039503 · DOI
  25. Jaffee SR, Price TS. 2007. Gene-environment correlations: a review of the evidence and implications for prevention of mental illness. Mol Psychiatry 12: 432-442. doi:10.1038/sj .mp.4001950 · DOI
  26. Keller MC, Medland SE, Duncan LE, Hatemi PK, Neale MC, Maes HHM, Eaves LJ. 2009. Modeling extended twin family data I: description of the cascade model. Twin Res Hum Genet 12: 8-18. doi:10.1375/twin.12.1.8 · DOI
  27. Kendler KS, Baker JH. 2007. Genetic influences on measures of the environment: a systematic review. Psychol Med 37: 615-626. doi:10.1017/S0033291706009524 · DOI · Paper page
  28. Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ. 1993. A test of the equal-environment assumption in twin studies of psychiatric illness. Behav Genet 23: 21-27. doi:10.1007/BF01067551 · DOI
  29. Kendler KS, Jacobson KC, Gardner CO, Gillespie N, Aggen SA, Prescott CA. 2007. Creating a social world: a devel- opmental twin study of peer-group deviance. Arch Gen Psychiatry 64: 958-965. doi:10.1001/archpsyc.64.8.958 · DOI
  30. Kendler KS, Jacobson K, Myers J, Eaves L. 2008. A genetically informative developmental study of the relationship between conduct disorder and peer deviance in males. Psychol Med 38: 1001-1011. doi:10.1017/S003329170 7001821 · DOI · Paper page
  31. Kong A, Thorleifsson G, Frigge ML, Vilhjalmsson BJ, Young AI, Thorgeirsson TE, Benonisdottir S, Oddsson A, Hall- dorsson BV, Masson G, et al. 2018. The nature of nurture: effects of parental genotypes. Science 359: 424-428. doi:10.1126/science.aan6877 · DOI · Paper page
  32. Kuja-Halkola R, D'Onofrio BM, Larsson H, Lichtenstein P. 2014. Maternal smoking during pregnancy and adverse outcomes in offspring: genetic and environmental sourc- es of covariance. Behav Genet 44: 456-467. doi:10.1007/ s10519-014-9668-4 · DOI
  33. Lim KX, Liu CY, Schoeler T, Cecil CA, Barker ED, Viding E, Greven CU, Pingault JB. 2018. The role of birth weight on the causal pathway to child and adolescent ADHD symp- tomatology: a population-based twin differences longitu- dinal design. J Child Psychol Psychiatry 59: 1036-1043. doi:10.1111/jcpp.12949 · DOI
  34. Luo YL, Haworth CM, Plomin R. 2010. A novel approach to genetic and environmental analysis of cross-lagged asso- ciations over time: the cross-lagged relationship between self-perceived abilities and school achievement is mediat- ed by genes as well as the environment. Twin Res Hum Genet 13: 426-436. doi:10.1375/twin.13.5.426 · DOI
  35. Ã Lynch K. 2020. The meaning of "cause" in genetics. Cold Spring Harb Perspect Med doi: 10.1101/cshperspect .a040519 · DOI
  36. Maes HH, Neale MC, Medland SE, Keller MC, Martin NG, Heath AC, Eaves LJ. 2009. Flexible Mx specification of various extended twin kinship designs. Twin Res Hum Genet 12: 26-34. doi:10.1375/twin.12.1.26 · DOI
  37. Malanchini M, Wang Z, Voronin I, Schenker VJ, Plomin R, Petrill SA, Kovas Y. 2017. Reading self-perceived ability, enjoyment and achievement: a genetically informative study of their reciprocal links over time. Dev Psychol 53: 698-712. doi:10.1037/dev0000209 · DOI
  38. McAdams TA, Neiderhiser JM, Rijsdijk FV, Narusyte J, Lichtenstein P, Eley TC. 2014. Accounting for genetic and environmental confounds in associations between parent and child characteristics: a systematic review of children-of-twins studies. Psychol Bull 140: 1138-1173. doi: 10.1037/a0036416. · DOI
  39. McAdams TA, Hannigan LJ, Eilertsen EM, Gjerde LC, Ystrom E, Rijsdijk FV. 2018. Revisiting the children-of- twins design: improving existing models for the explora- Twins and Causal Inference Cite this article as Cold Spring Harb Perspect Med 2021;11:a039552 tion of intergenerational associations. Behav Genet 48: 397-412. doi:10.1007/s10519-018-9912-4 · DOI
  40. Millwood IY, Walters RG, Mei XW, Guo Y, Yang L, Bian Z, Bennett DA, Chen Y, Dong C, Hu R, et al. 2019. Conven- tional and genetic evidence on alcohol and vascular dis- ease aetiology: a prospective study of 500,000 men and women in China. Lancet 393: 1831-1842. doi:10.1016/ S0140-6736(18)31772-0 · DOI · Paper page
  41. Narusyte J, Neiderhiser JM, D'Onofrio BM, Reiss D, Spotts EL, Ganiban J, Lichtenstein P. 2008. Testing different types of genotype-environment correlation: an extended children-of-twins model. Dev Psychol 44: 1591-1603. doi:10.1037/a0013911 · DOI
  42. Neiderhiser JM, Reiss D, Pedersen NL, Lichtenstein P, Spotts EL, Hansson K, Cederblad M, Ellhammer O. 2004. Ge- netic and environmental influences on mothering of ad- olescents: a comparison of two samples. Dev Psychol 40: 335-351. doi:10.1037/0012-1649.40.3.335 · DOI
  43. Neiderhiser JM, Reiss D, Hetherington EM. 2007a. The Nonshared Environment in Adolescent Development (NEAD) Project: a longitudinal family study of twins and siblings from adolescence to young adulthood. Twin Res Hum Genet 10: 74-83. doi:10.1375/twin.10.1.74 · DOI
  44. Neiderhiser JM, Reiss D, Lichtenstein P, Spotts EL, Ganiban J. 2007b. Father-adolescent relationships and the role of genotype-environment correlation. J Fam Psychol 21: 560-571. doi:10.1037/0893-3200.21.4.560 · DOI
  45. Ozaki K, Ando J. 2009. Direction of causation between shared and non-shared environmental factors. Behav Ge- net 39: 321-336. doi:10.1007/s10519-009-9257-0 · DOI
  46. Pingault JB, O'reilly PF, Schoeler T, Ploubidis GB, Rijsdijk F, Dudbridge F. 2018. Using genetic data to strengthen caus- al inference in observational research. Nat Rev Genet 19: 566-580. doi:10.1038/s41576-018-0020-3 · DOI · Paper page
  47. Plomin R, DeFries JC, Knopik VS, Neiderhiser JM. 2016. Top 10 replicated findings from behavioral genetics. Per- spect Psychol Sci 11: 3-23. doi:10.1177/1745691615 617439 · DOI · Paper page
  48. Rice F, van den Bree MBM, Thapar A. 2004. A population- based study of anxiety as a precursor for depression in childhood and adolescence. BMC Psychiatry 4: 43. doi:10 .1186/1471-244X-4-43 · DOI
  49. Ã Richmond R. 2020. Mendelian randomization: concepts and scope. Cold Spring Harb Perspect Med doi: 10.1101/ cshperspect.a040501 · DOI · Paper page
  50. Selzam S, McAdams TA, Coleman JR, Carnell S, O'Reilly PF, Plomin R, Llewellyn CH. 2018. Evidence for gene-envi- ronment correlation in child feeding: links between com- mon genetic variation for BMI in children and parental feeding practices. PLoS Genet 14: e1007757. doi:10.1371/ journal.pgen.1007757 · DOI
  51. Silberg JL, Eaves LJ. 2004. Analysing the contributions of genes and parent-child interaction to childhood behav- ioural and emotional problems: a model for the children of twins. Psychol Med 34: 347-356. doi:10.1017/ S0033291703008948 · DOI
  52. Silberg JL, Maes H, Eaves LJ. 2010. Genetic and environmen- tal influences on the transmission of parental depression to children's depression and conduct disturbance: an ex- tended children of twins study. J Child Psychol Psychiatry 51: 734-744. doi:10.1111/j.1469-7610.2010.02205.x · DOI
  53. Silberg JL, Copeland W, Linker J, Moore AA, Roberson-Nay R, York TP. 2016. Psychiatric outcomes of bullying vic- timization: a study of discordant monozygotic twins. Psy- chol Med 46: 1875-1883. doi:10.1017/S00332917160 00362 · DOI · Paper page
  54. Singham T, Viding E, Schoeler T, Arseneault L, Ronald A, Cecil CM, McCrory E, Rijsdijk F, Pingault JB. 2017. Con- current and longitudinal contribution of exposure to bullying in childhood to mental health: the role of vul- nerability and resilience. JAMA Psychiatry 74: 1112- 1119. doi:10.1001/jamapsychiatry.2017.2678 · DOI
  55. Smith GD. 2011. Epidemiology, epigenetics and the "gloomy prospect": embracing randomness in population health research and practice. Int J Epidemiol 40: 537-562. doi:10.1093/ije/dyr117 · DOI
  56. Tick B, Colvert E, McEwen F, Stewart C, Woodhouse E, Gillan N, Hallett V, Lietz S, Garnett T, Simonoff E, et al. 2016. Autism spectrum disorders and other mental health problems: exploring etiological overlaps and phe- notypic causal associations. J Am Acad Child Adolesc Psy- chiatry 55: 106-113.e4. doi:10.1016/j.jaac.2015.11.013 · DOI · Paper page
  57. Tikhodeyev ON, Shcherbakova ОV. 2019. The problem of non-shared environment in behavioral genetics. Behav Genet 49: 259-269. doi:10.1007/s10519-019-09950-1 · DOI
  58. Torvik FA, Rosenström TH, Ystrom E, Tambs K, Røysamb E, Czajkowski N, Gillespie N, Knudsen GP, Kendler KS, Reichborn-Kjennerud T. 2017. Stability and change in etiological factors for alcohol use disorder and major de- pression. J Abnorm Psychol 126: 812-822. doi:10.1037/ abn0000280 · DOI
  59. Torvik FA, Rosenström TH, Gustavson K, Ystrom E, Ken- dler KS, Bramness JG, Czajkowski N, Reichborn-Kjen- nerud T. 2019. Explaining the association between anxi- ety disorders and alcohol use disorder: a twin study. Depress Anxiety 36: 522-532. doi:10.1002/da.22886 · DOI
  60. Torvik FA, Eilertsen EM, McAdams TA, Gustavson K, Zach- risson HD, Brandlistuen R, Gjerde LC, Havdahl A, Stol- tenberg C, Ask H, et al. 2020. Mechanisms linking paren- tal educational attainment with child ADHD, depression, and academic problems: a study of extended families in The Norwegian Mother, Father and Child Cohort Study. J Child Psychol Psychiatry doi:10.1111/jcpp.13197 · DOI
  61. Truett KR, Eaves LJ, Walters EE, Heath AC, Hewitt JK, Meyer JM, Silberg J, Neale MC, Martin NG, Kendler KS. 1994. A model system for analysis of family resem- blance in extended kinships of twins. Behav Genet 24: 35- 49. doi:10.1007/BF01067927 · DOI
  62. Turkheimer E, Harden KP. 2014. Behavior genetic research methods: testing quasi-causal hypotheses using multivar- iate twin data. In Handbook of research methods in social and personality psychology (ed. Reis HT), pp. 159-187. Cambridge University Press, Cambridge.
  63. Verhulst B. 2017. A power calculator for the classical twin design. Behav Genet 47: 255-261. doi:10.1007/s10519- 016-9828-9 · DOI
  64. Visscher PM. 2004. Power of the classical twin design revis- ited. Twin Res Hum Genet 7: 505-512. doi:10.1375/ 1369052042335250 · DOI
  65. Xu C, Sun J, Ji F, Tian X, Duan H, Zhai Y, Wang S, Pang Z, Zhang D, Zhao Z, et al. 2015. The genetic basis for cog- nitive ability, memory, and depression symptomatology in middle-aged and elderly Chinese twins. Twin Res Hum Genet 18: 79-85. doi:10.1017/thg.2014. · DOI
  66. Ystrom E, Eilertsen EM. 2019. Deconstructing the history of genotype-phenotype associations in humans. Science. Available at https://science.sciencemag.org/content/365/ 6460/1396/tab-e-letters Twins and Causal Inference Cite this article as Cold Spring Harb Perspect Med 2021;11:

Cited by

Sorted by citations

Authors
McAdams, T. A., Rijsdijk, F. V., Zavos, H. M. S., & Pingault, J.-B.
Affiliations
King's College London (GB)
ORCID
Venue
Cold Spring Harbor Perspectives in Medicine
Publisher
Cold Spring Harbor Laboratory
Published
2020-09-08
Volume
11
Issue
6
Pages
a039552
ISSN
2157-1422 (ISSN-L)
DOI
10.1101/cshperspect.a039552
PMC
PMC8168524
OpenAlex
W3084427207
Cited by
74
References
10
Citations by year
2026: 11 · 2025: 14 · 2024: 18 · 2023: 20 · 2022: 4 · 2021: 5 · 2020: 2
Type
posted content
Language
en
Open access
Locations
  • Cold Spring Harbor Perspectives in Medicine (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (submittedVersion, other-oa)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Wellcome Trust (107706/Z/15/Z, /Z/15/Z)
  • MQ: Transforming Mental Health (MQ16IP16)
  • Royal Society (107706/Z/15/Z)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Assisted Reproductive Technology and Twin Pregnancy
  • Physical Sciences › Mathematics › Statistics and Probability › Advanced Causal Inference Techniques
Keywords
twin studies, causal inference, monozygotic twins, dizygotic twins, shared environment, nonshared environment, genetic factors, common cause, causal direction, intergenerational associations
MeSH terms
Disease, Environmental Exposure, Humans, Twins, Dizygotic, Twins, Monozygotic

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review