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Maternal half-sibling families with discordant fathers: a contrastive design assessing cross-generational paternal genetic transmission of alcohol use disorder, drug abuse and major depression

  • Kenneth S. Kendler (a1) (a2) (a3), Henrik Ohlsson (a4), Jan Sundquist (a4) (a5) (a6) and Kristina Sundquist (a4) (a5) (a6)

We introduce and apply an elegant, contrastive genetic-epidemiological design – Maternal Half-Sibling Families with Discordant Fathers – to clarify cross-generational transmission of genetic risk to alcohol use disorder (AUD), drug abuse (DA) and major depression (MD).


Using Swedish national registries, we identified 73 108 eligible pairs of reared together maternal half-siblings and selected those whose biological fathers were discordant for AUD, DA and MD, and had minimal contact with the affected father. We examined differences in outcome in half-siblings with an affected v. unaffected father.


For AUD, DA and MD, the HR (95% confidence intervals) for the offspring of affected v. unaffected fathers were, respectively, 1.72 (1.61; 1.84), 1.55 (1.41; 1.70) and 1.51 (1.40; 1.64). Paternal DA and AUD, but not MD, predicted risk in offspring for attention deficit hyperactivity disorder, conduct disorder, and poor educational performance and attainment. Offspring of affected v. unaffected fathers had poorer pregnancy outcomes, with the effect strongest for DA and weakest for MD. A range of potential biases and confounders were examined and were not found to alter these findings substantially.


Reared together maternal half-siblings differ in their paternal genetic endowment, sharing the same mother, family, school and community. They can help clarify the nature of paternal genetic effects and produce results consistent with other designs. Paternal genetic risk for DA and AUD have effects on offspring educational achievement, child and adult psychopathology, and possibly prenatal development. The impact of paternal genetic risk for MD is narrower in scope.

Corresponding author
Author for correspondence: Kenneth S. Kendler, E-mail:
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Beidler, E, Covassin, T, Donnellan, MB, Nogle, S, Pontifex, MB and Kontos, AP (2017) Higher risk-taking behavioursbehaviors and sensation seeking needs in collegiate student-athletes with a history of multiple sport-related concussions. British Journal of Sports Medicine 51, A66. Abstract.
Cadoret, RJ (1978) Evidence for genetic inheritance of primary affective disorder in adoptees. American Journal of Psychiatry 135, 463466.
Cadoret, R (1986) Adoption studies: historical and methodological critique. Psychiatric Developments 1, 4564.
Cadoret, RJ, Troughton, E, O'Gorman, TW and Heywood, E (1986) An adoption study of genetic and environmental factors in drug abuse. Archives of General Psychiatry 43, 11311136.
Cadoret, RJ, Yates, WR, Troughton, E, Woodworth, G and Stewart, MA (1995) Adoption study demonstrating two genetic pathways to drug abuse. Archives of General Psychiatry 52, 4252.
Edwards, AC and Kendler, KS (2012) Twin study of the relationship between adolescent attention-deficit/hyperactivity disorder and adult alcohol dependence. Journal of Studies of Alcohol and Drugs 73, 185194.
Edwards, M, Witt, A, Dawson, S, Harkey, C and Bui, K (2018) Premorbid ADHD and concussion in pediatric population. American Academy of Neurology 90(15 Suppl.), P6.297. Abstract.
Goodwin, DW (1981) Adoption studies of alcoholism. Progress in Clinical and Biological Research 69, Pt C, 7176.
Kendler, KS, Prescott, CA, Myers, J and Neale, MC (2003) The structure of genetic and environmental risk factors for common psychiatric and substance use disorders in men and women. Archives of General Psychiatry 60, 929937.
Kendler, KS, Gatz, M, Gardner, C and Pedersen, N (2006) A Swedish national twin study of lifetime major depression. American Journal of Psychiatry 163, 109114.
Kendler, KS, Aggen, SH, Knudsen, GP, Roysamb, E, Neale, MC and Reichborn-Kjennerud, T (2011) The structure of genetic and environmental risk factors for syndromal and subsyndromal common DSM-IV axis I and all axis II disorders. American Journal of Psychiatry 168, 2939.
Kendler, KS, Sundquist, K, Ohlsson, H, Palmer, K, Maes, H, Winkleby, MA and Sundquist, J (2012) Genetic and familial environmental influences on the risk for drug abuse: a national Swedish adoption study. Archives of General Psychiatry 69, 690697.
Kendler, KS, Maes, HH, Sundquist, K, Ohlsson, H and Sundquist, J (2013) Genetic and family and community environmental effects on drug abuse in adolescence: a Swedish national twin and sibling study. American Journal of Psychiatry 171, 209217.
Kendler, KS, Ji, J, Edwards, AC, Ohlsson, H, Sundquist, J and Sundquist, K (2015 a) An extended Swedish national adoption study of alcohol use disorder. JAMA Psychiatry 72, 211218.
Kendler, KS, Ohlsson, H, Sundquist, J and Sundquist, K (2015 b) Triparental families: a new genetic-epidemiological design applied to drug abuse, alcohol use disorders, and criminal behavior in a Swedish national sample. American Journal of Psychiatry 172, 553560.
Kendler, KS, Lonn, SL, Maes, HH, Lichtenstein, P, Sundquist, J and Sundquist, K (2016 a) A Swedish population-based multivariate twin study of externalizing disorders. Behavior Genetics 46, 183192.
Kendler, KS, Ohlsson, H, Sundquist, K and Sundquist, J (2016 b) Cross-generational transmission from drug abuse in parents to attention-deficit/hyperactivity disorder in children. Psychological Medicine 46, 13011309.
Kendler, KS, Ohlsson, H, Sundquist, K and Sundquist, J (2018) Sources of parent-offspring resemblance for major depression in a national Swedish extended adoption study. JAMA Psychiatry 75, 194200.
Kendler, KS, Ohlsson, H, Sundquist, J and Sundquist, K (2019) Parent-offspring transmission of drug abuse and alcohol use disorder: application of the multiple parenting relationships design. American Journal of Medical Genetics Part B Neuropsychiatric Genetics March 1 [epub].
Kessler, RC, Berglund, P, Demler, O, Jin, R, Koretz, D, Merikangas, KR, Rush, AJ, Walters, EE and Wang, PS (2003) The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). Journal of the American Medical Association 289, 30953105.
Kringlen, E, Torgersen, S and Cramer, V (2001) A Norwegian psychiatric epidemiological study. American Journal of Psychiatry 158, 10911098.
Latvala, A, Kuja-Halkola, R D'Onofrio, BM, Larsson, H and Lichtenstein, P (2016) Cognitive ability and risk for substance misuse in men: genetic and environmental correlations in a longitudinal nation-wide family study. Addiction 111, 18141822.
Lewis, G, Rice, F, Harold, GT, Collishaw, S and Thapar, A (2011) Investigating environmental links between parent depression and child depressive/anxiety symptoms using an assisted conception design. Journal of the American Academy of Child and Adolescent Psychiatry 50, 451459.
McAdams, TA, Neiderhiser, JM, Rijsdijk, FV, Narusyte, J, Lichtenstein, P and Eley, TC (2014) Accounting for genetic and environmental confounds in associations between parent and child characteristics: a systematic review of children-of-twins studies. Psychological Bulletin 140, 11381173.
Munafo, MR and Davey, SG (2018) Robust research needs many lines of evidence. Nature 553, 399401.
Mutsaerts, MA, Groen, H, Buiter-Van der Meer, A, Sijtsma, A, Sauer, PJ, Land, JA, Mol, BW, Corpeleijn, E and Hoek, A (2014) Effects of paternal and maternal lifestyle factors on pregnancy complications and perinatal outcome. A population-based birth-cohort study: the GECKO Drenthe cohort. Human Reproduction 29, 824834.
Passaro, KT, Little, RE, Savitz, DA and Noss, J (1998) Effect of paternal alcohol consumption before conception on infant birth weight. ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. Teratology 57, 294301.
SAS Institute (2012) I. SAS/STAT® Online Documentation, Version 9.4. Cary, N.C.: SAS Institute, Inc.
Shah, PS (2010) Paternal factors and low birthweight, preterm, and small for gestational age births: a systematic review. American Journal of Obstetrics and Gynecology 202, 103123.
Shah, MK, Gee, RE and Theall, KP (2014) Partner support and impact on birth outcomes among teen pregnancies in the United States. Journal of Pediatric and Adolescent Gynecology 27, 1419.
Sigvardsson, S, Bohman, M and Cloninger, CR (1996) Replication of the Stockholm Adoption Study of alcoholism. Confirmatory cross-fostering analysis. Archives of General Psychiatry 53, 681687.
Walters, RK, Polimanti, R, Johnson, EC, McClintick, JN, Adams, MJ, Adkins, AE, Aliev, F, Bacanu, SA, Batzler, A, Bertelsen, S, Biernacka, JM, Bigdeli, TB, Chen, LS, Clarke, TK, Chou, YL, Degenhardt, F, Docherty, AR, Edwards, AC, Fontanillas, P, Foo, JC, Fox, L, Frank, J, Giegling, I, Gordon, S, Hack, LM, Hartmann, AM, Hartz, SM, Heilmann-Heimbach, S, Herms, S, Hodgkinson, C, Hoffmann, P, Jan, HJ, Kennedy, MA, Alanne-Kinnunen, M, Konte, B, Lahti, J, Lahti-Pulkkinen, M, Lai, D, Ligthart, L, Loukola, A, Maher, BS, Mbarek, H, McIntosh, AM, McQueen, MB, Meyers, JL, Milaneschi, Y, Palviainen, T, Pearson, JF, Peterson, RE, Ripatti, S, Ryu, E, Saccone, NL, Salvatore, JE, Sanchez-Roige, S, Schwandt, M, Sherva, R, Streit, F, Strohmaier, J, Thomas, N, Wang, JC, Webb, BT, Wedow, R, Wetherill, L, Wills, AG, Boardman, JD, Chen, D, Choi, DS, Copeland, WE, Culverhouse, RC, Dahmen, N, Degenhardt, L, Domingue, BW, Elson, SL, Frye, MA, Gabel, W, Hayward, C, Ising, M, Keyes, M, Kiefer, F, Kramer, J, Kuperman, S, Lucae, S, Lynskey, MT, Maier, W, Mann, K, Mannisto, S, Muller-Myhsok, B, Murray, AD, Nurnberger, JI, Palotie, A, Preuss, U, Raikkonen, K, Reynolds, MD, Ridinger, M, Scherbaum, N, Schuckit, MA, Soyka, M, Treutlein, J, Witt, S, Wodarz, N, Zill, P, Adkins, DE, Boden, JM, Boomsma, DI, Bierut, LJ, Brown, SA, Bucholz, KK, Cichon, S, Costello, EJ, de, WH, Diazgranados, N, Dick, DM, Eriksson, JG, Farrer, LA, Foroud, TM, Gillespie, NA, Goate, AM, Goldman, D, Grucza, RA, Hancock, DB, Harris, KM, Heath, AC, Hesselbrock, V, Hewitt, JK, Hopfer, CJ, Horwood, J, Iacono, W, Johnson, EO, Kaprio, JA, Karpyak, VM, Kendler, KS, Kranzler, HR, Krauter, K, Lichtenstein, P, Lind, PA, McGue, M, MacKillop, J, Madden, PAF, Maes, HH, Magnusson, P, Martin, NG, Medland, SE, Montgomery, GW, Nelson, EC, Nothen, MM, Palmer, AA, Pedersen, NL, Penninx, BWJH, Porjesz, B, Rice, JP, Rietschel, M, Riley, BP, Rose, R, Rujescu, D, Shen, PH, Silberg, J, Stallings, MC, Tarter, RE, Vanyukov, MM, Vrieze, S, Wall, TL, Whitfield, JB, Zhao, H, Neale, BM, Gelernter, J, Edenberg, HJ and Agrawal, A (2018) Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders. Nature Neuroscience 21, 16561669.
Wender, PH, Kety, SS, Rosenthal, D, Schulsinger, F, Ortmann, J and Lunde, I (1986) Psychiatric disorders in the biological and adoptive families of adopted individuals with affective disorders. Archives of General Psychiatry 43, 923929.
Wikipedia contributors (2019) Adoption. Primary contributors: Revision history statistics. Page Version ID: 888708443 . 3-20-2019. Wikipedia, The Free Encyclopedia. 3-21-2019. Electronic Citation.
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