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The positive end of the polygenic score distribution for ADHD: a low risk or a protective factor?

Published online by Cambridge University Press:  29 October 2019

James J. Li*
Waisman Center and University of Wisconsin-Madison, Madison, WI, USA
Author for correspondence: James J. Li, E-mail:



Polygenic scores (PGS) are widely used to characterize genetic liability for heritable mental disorders, including attention-deficit/hyperactivity disorder (ADHD). However, little is known about the effects of a low burden of genetic liability for ADHD, including whether this functions as a low risk or protective factor for ADHD and related functional outcomes in later life. The current study examines the association of low ADHD PGS and functional outcomes in adulthood.


Participants were from Wave IV of the National Longitudinal Study of Adolescent to Adult Health (Add Health) (N = 7088; mean age = 29, s.d. = 1.74). ADHD PGS was computed from an existing genome-wide association study, and adult functional outcomes, including cognition, educational attainment, mental health, and physical health were assessed during in-home interviews.


Individuals at the lowest end of the ADHD PGS distribution (i.e. lowest 20th percentile) had the lowest probabilities of ADHD, exhibiting a 17–19% reduction in risk for ADHD relative to the observed 8.3% prevalence rate of ADHD in Add Health. Furthermore, individuals with low ADHD PGS had higher cognitive performance, greater levels of educational attainment, and lower BMI relative to individuals representing the rest of the ADHD PGS distribution, including those who were in the medium and high-PGS groups.


Findings indicate that psychiatric PGS likely capture far more than just the risk and the absence of risk for a psychiatric outcome; where one lies along the PGS distribution may predict diverging functional consequences, for better and for worse.

Original Articles
Copyright © Cambridge University Press 2019

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Adler, LA, Spencer, T, Faraone, SV, Kessler, RC, Howes, MJ, Biederman, J and Secnik, K (2006) Validity of pilot adult ADHD Self- Report Scale (ASRS) to rate adult ADHD symptoms. Annals of Clinical Psychiatry 18, 145148.CrossRefGoogle ScholarPubMed
Agnew-Blais, JC, Polanczyk, GV, Danese, A, Wertz, J, Moffitt, TE and Arseneault, L (2018) Young adult mental health and functional outcomes among individuals with remitted, persistent and late-onset ADHD. The British Journal of Psychiatry 213, 526534.CrossRefGoogle ScholarPubMed
American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental Disorders, 5th Edn. Washington, DC: Author.Google Scholar
Anderson, JS, Shade, J, DiBlasi, E, Shabalin, AA and Docherty, AR (2019) Polygenic risk scoring and prediction of mental health outcomes. Current Opinion in Psychology 27, 7781.CrossRefGoogle ScholarPubMed
Benjamini, Y, Drai, D, Elmer, G, Kafkafi, N and Golani, I (2001) Controlling the false discovery rate in behavior genetics research. Behavioural Brain Research 125, 279284.CrossRefGoogle ScholarPubMed
Bogdan, R, Baranger, DAA and Agrawal, A (2018) Polygenic risk scores in clinical psychology: bridging genomic risk to individual differences. Annual Review of Clinical Psychology 14, 119157.CrossRefGoogle ScholarPubMed
Boonstra, AM, Oosterlaan, J, Sergeant, JA and Buitelaar, JK (2005) Executive functioning in adult ADHD: a meta-analytic review. Psychological Medicine 35, 10971108.CrossRefGoogle ScholarPubMed
Braudt, D and Harris, K (2018) Polygenic scores (PGSs) in the national longitudinal study of adolescent to adult health (Add Health) – Release 1. Carolina Digital Repository, 172. Scholar
Brook, JS, Brook, DW, Zhang, C, Seltzer, N and Finch, SJ (2013) Adolescent ADHD and adult physical and mental health, work performance, and financial stress. Pediatrics 131, 513.CrossRefGoogle ScholarPubMed
Chang, Z, Lichtenstein, P, Asherson, PJ and Larsson, H (2013) Developmental twin study of attention problems: high heritabilities throughout development. JAMA Psychiatry 70, 311318.CrossRefGoogle ScholarPubMed
Cohen, S, Kamarck, T and Mermelstein, R (1983) A global measure of perceived stress. Journal of Health and Social Behavior 24, 385396.CrossRefGoogle ScholarPubMed
Combs, MA, Canu, WH, Broman-Fulks, JJ, Rocheleau, CA and Nieman, DC (2015) Perceived stress and ADHD symptoms in adults. Journal of Attention Disorders 19, 425434.CrossRefGoogle ScholarPubMed
Danielson, ML, Bitsko, RH, Ghandour, RM, Holbrook, JR, Kogan, MD and Blumberg, SJ (2018) Prevalence of parent-reported ADHD diagnosis and associated treatment among U.S. children and adolescents, 2016. Journal of Clinical Child and Adolescent Psychology 47, 199212.CrossRefGoogle Scholar
Demontis, D, Walters, RK, Martin, J, Mattheisen, M, Als, TD, Agerbo, E, Baldursson, G, Belliveau, R, Bybjerg-Grauholm, J, Bækvad-Hansen, M, Cerrato, F, Chambert, K, Churchhouse, C, Dumont, A, Eriksson, N, Gandal, M, Goldstein, JI, Grasby, KL, Grove, J, Gudmundsson, OO, Hansen, CS, Hauberg, ME, Hollegaard, MV, Howrigan, DP, Huang, H, Maller, JB, Martin, AR, Martin, NG, Moran, J, Pallesen, J, Palmer, DS, Pedersen, CB, Pedersen, MG, Poterba, T, Poulsen, JB, Ripke, S, Robinson, EB, Satterstrom, FK, Stefansson, H, Stevens, C, Turley, P, Walters, GB, Won, H, Wright, MJ, Andreassen, OA, Asherson, P, Burton, CL, Boomsma, DI, Cormand, B, Dalsgaard, S, Franke, B, Gelernter, J, Geschwind, D, Hakonarson, H, Haavik, J, Kranzler, HR, Kuntsi, J, Langley, K, Lesch, K-P, Middeldorp, C, Reif, A, Rohde, LA, Roussos, P, Schachar, R, Sklar, P, Sonuga-Barke, EJS, Sullivan, PF, Thapar, A, Tung, JY, Waldman, ID, Medland, SE, Stefansson, K, Nordentoft, M, Hougaard, DM, Werge, T, Mors, O, Mortensen, PB, Daly, MJ, Faraone, SV, Børglum, AD and Neale, BM (2019) Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nature Genetics 51, 63.CrossRefGoogle ScholarPubMed
Du Rietz, E, Coleman, J, Glanville, K, Choi, SW, O'Reilly, PF and Kuntsi, J (2017) Association of polygenic risk for attention-deficit/hyperactivity disorder with co-occurring traits and disorders. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging 3, 635643.Google ScholarPubMed
Dudbridge, F (2013) Power and predictive accuracy of polygenic risk scores. PLOS Genetics 9, e1003348.CrossRefGoogle ScholarPubMed
Faraone, SV and Larsson, H (2019) Genetics of attention deficit hyperactivity disorder. Molecular Psychiatry, 24, 562575.CrossRefGoogle ScholarPubMed
Fletcher, J and Wolfe, B (2009) Long-term consequences of childhood ADHD on criminal activities. The Journal of Mental Health Policy and Economics 12, 119138.Google ScholarPubMed
Franke, B, Neale, BM and Faraone, SV (2009) Genome-wide association studies in ADHD. Human Genetics 126, 1350.CrossRefGoogle ScholarPubMed
Groen-Blokhuis, MM, Middeldorp, CM, Kan, K-J, Abdellaoui, A, van Beijsterveldt, CEM, Ehli, EA, Davies, GE, Scheet, PA, Xiao, X, Hudziak, JJ, Hottenga, J-J, Neale, BM and Boomsma, DI (2014) Attention-deficit/hyperactivity disorder polygenic risk scores predict attention problems in a population-based sample of children. Journal of the American Academy of Child & Adolescent Psychiatry 53, 11231129, e6.CrossRefGoogle Scholar
Hamshere, ML, Langley, K, Martin, J, Agha, SS, Stergiakouli, E, Anney, RJL, Buitelaar, J, Faraone, SV, Lesch, K-P, Neale, BM, Franke, B, Sonuga-Barke, E, Asherson, P, Merwood, A, Kuntsi, J, Medland, SE, Ripke, S, Steinhausen, H-C, Freitag, C, Reif, A, Renner, TJ, Romanos, M, Romanos, J, Warnke, A, Meyer, J, Palmason, H, Vasquez, AA, Lambregts-Rommelse, N, Roeyers, H, Biederman, J, Doyle, AE, Hakonarson, H, Rothenberger, A, Banaschewski, T, Oades, RD, McGough, JJ, Kent, L, Williams, N, Owen, MJ, Holmans, P, O'Donovan, MC and Thapar, A (2013) High loading of polygenic risk for ADHD in children with comorbid aggression. American Journal of Psychiatry 170, 909916.CrossRefGoogle ScholarPubMed
Khera, AV, Chaffin, M, Aragam, KG, Haas, ME, Roselli, C, Choi, SH, Natarajan, P, Lander, ES, Lubitz, SA, Ellinor, PT and Kathiresan, S (2018) Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nature Genetics 50, 1219.CrossRefGoogle ScholarPubMed
Knopik, V, Neiderhiser, JM, DeFries, JC and Plomin, R (2016) Behavioral Genetics, 7th Edn. New York: Worth.Google ScholarPubMed
Kooij, JJS, Boonstra, AM, Swinkels, SHN, Bekker, EM, de Noord, I and Buitelaar, JK (2008) Reliability, validity, and utility of instruments for self-report and informant report concerning symptoms of ADHD in adult patients. Journal of Attention Disorders 11, 445458.CrossRefGoogle Scholar
Krapohl, E, Euesden, J, Zabaneh, D, Pingault, J-B, Rimfeld, K, von Stumm, S, Dale, PS, Breen, G, O'Reilly, PF and Plomin, R (2016) Phenome-wide analysis of genome-wide polygenic scores. Molecular Psychiatry 21, 11881193.CrossRefGoogle ScholarPubMed
Kuriyan, AB, Pelham, WE, Molina, BSG, Waschbusch, DA, Gnagy, EM, Sibley, MH, Babinski, DE, Walther, C, Cheong, J, Yu, J and Kent, KM (2013) Young adult educational and vocational outcomes of children diagnosed with ADHD. Journal of Abnormal Child Psychology 41, 2741.CrossRefGoogle ScholarPubMed
Larsson, H, Asherson, P, Chang, Z, Ljung, T, Friedrichs, B, Larsson, J-O and Lichtenstein, P (2013) Genetic and environmental influences on adult attention deficit hyperactivity disorder symptoms: a large Swedish population-based study of twins. Psychological Medicine 43, 197207.CrossRefGoogle Scholar
Larsson, H, Chang, Z, D'Onofrio, BM and Lichtenstein, P (2014) The heritability of clinically diagnosed attention deficit hyperactivity disorder across the lifespan. Psychological Medicine 44, 22232229.CrossRefGoogle ScholarPubMed
Lee, SS, Humphreys, KL, Flory, K, Liu, R and Glass, K (2011) Prospective association of childhood attention-deficit/hyperactivity disorder (ADHD) and substance use and abuse/dependence: a meta-analytic review. Clinical Psychology Review 31, 328341.CrossRefGoogle ScholarPubMed
Mega, JL, Stitziel, NO, Smith, JG, Chasman, DI, Caulfield, MJ, Devlin, JJ, Nordio, F, Hyde, CL, Cannon, CP, Sacks, FM, Poulter, NR, Sever, PS, Ridker, PM, Braunwald, E, Melander, O, Kathiresan, S and Sabatine, MS (2015) Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials. Lancet 385, 22642271.CrossRefGoogle ScholarPubMed
Merwood, A, Greven, CU, Price, TS, Rijsdijk, F, Kuntsi, J, McLoughlin, G, Larsson, H and Asherson, PJ (2013) Different heritabilities but shared etiological influences for parent, teacher and self-ratings of ADHD symptoms: an adolescent twin study. Psychological Medicine 43, 19731984.CrossRefGoogle ScholarPubMed
Mullins, N, Power, RA, Fisher, HL, Hanscombe, KB, Euesden, J, Iniesta, R, Levinson, DF, Weissman, MM, Potash, JB, Shi, J, Uher, R, Cohen-Woods, S, Rivera, M, Jones, L, Jones, I, Craddock, N, Owen, MJ, Korszun, A, Craig, IW, Farmer, AE, McGuffin, P, Breen, G and Lewis, CM (2016) Polygenic interactions with environmental adversity in the aetiology of major depressive disorder. Psychological Medicine 46, 759770.CrossRefGoogle ScholarPubMed
Natarajan, P, Young, R, Stitziel Nathan, O, Padmanabhan, S, Baber, U, Mehran, R, Sartori, S, Fuster, V, Reilly Dermot, F, Butterworth, A, Rader Daniel, J, Ford, I, Sattar, N and Kathiresan, S (2017) Polygenic risk score identifies subgroup with higher burden of atherosclerosis and greater relative benefit from statin therapy in the primary prevention setting. Circulation 135, 20912101.CrossRefGoogle ScholarPubMed
Nikolas, MA and Burt, SA (2010) Genetic and environmental influences on ADHD symptom dimensions of inattention and hyperactivity: a meta-analysis. Journal of Abnormal Psychology 119, 117.CrossRefGoogle ScholarPubMed
Peyrot, WJ, Milaneschi, Y, Abdellaoui, A, Sullivan, PF, Hottenga, JJ, Boomsma, DI and Penninx, BWJH (2014) Effect of polygenic risk scores on depression in childhood trauma. The British Journal of Psychiatry 205, 113119.CrossRefGoogle ScholarPubMed
Plomin, R, Haworth, CMA and Davis, OSP (2009) Common disorders are quantitative traits. Nature Reviews Genetics 10, 872878.CrossRefGoogle ScholarPubMed
Price, AL, Patterson, NJ, Plenge, RM, Weinblatt, ME, Shadick, NA and Reich, D (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nature Genetics 38, 904909.CrossRefGoogle ScholarPubMed
Radloff, LS (1977) The CES-D scale: a self-report depression scale for research in the general population. Applied Psychological Measurement 1, 385401.CrossRefGoogle Scholar
Riglin, L, Collishaw, S, Thapar, AK, Dalsgaard, S, Langley, K, Smith, GD, Stergiakouli, E, Maughan, B, O'Donovan, MC and Thapar, A (2016) Association of genetic risk variants with attention-deficit/hyperactivity disorder trajectories in the general population. JAMA Psychiatry 73, 12851292.CrossRefGoogle ScholarPubMed
Rutter, M and Sroufe, LA (2000) Developmental psychopathology: concepts and challenges. Development and Psychopathology 12, 265296.CrossRefGoogle ScholarPubMed
Rutter, M, Simonoff, E and Plomin, R (1996) Genetic influences on mild mental retardation: concepts, findings and research implications. Journal of Biosocial Science 28, 509526.CrossRefGoogle ScholarPubMed
Stergiakouli, E, Martin, J, Hamshere, ML, Langley, K, Evans, DM, St Pourcain, B, Timpson, NJ, Owen, MJ, O'Donovan, M, Thapar, A and Davey Smith, G (2015) Shared genetic influences between attention-deficit/hyperactivity disorder (ADHD) traits in children and clinical ADHD. Journal of the American Academy of Child & Adolescent Psychiatry 54, 322327.CrossRefGoogle ScholarPubMed
Torkamani, A, Wineinger, NE and Topol, EJ (2018) The personal and clinical utility of polygenic risk scores. Nature Reviews Genetics 19, 581.CrossRefGoogle ScholarPubMed
Wray, NR, Ripke, S, Mattheisen, M, Trzaskowski, M, Byrne, EM, Abdellaoui, A, Adams, MJ, Agerbo, E, Air, TM, Andlauer, TMF, Bacanu, S-A, Bækvad-Hansen, M, Beekman, AFT, Bigdeli, TB, Binder, EB, Blackwood, DRH, Bryois, J, Buttenschøn, HN, Bybjerg-Grauholm, J, Cai, N, Castelao, E, Christensen, JH, Clarke, T-K, Coleman, JIR, Colodro-Conde, L, Couvy-Duchesne, B, Craddock, N, Crawford, GE, Crowley, CA, Dashti, HS, Davies, G, Deary, IJ, Degenhardt, F, Derks, EM, Direk, N, Dolan, CV, Dunn, EC, Eley, TC, Eriksson, N, Escott-Price, V, Kiadeh, FHF, Finucane, HK, Forstner, AJ, Frank, J, Gaspar, HA, Gill, M, Giusti-Rodríguez, P, Goes, FS, Gordon, SD, Grove, J, Hall, LS, Hannon, E, Hansen, CS, Hansen, TF, Herms, S, Hickie, IB, Hoffmann, P, Homuth, G, Horn, C, Hottenga, J-J, Hougaard, DM, Hu, M, Hyde, CL, Ising, M, Jansen, R, Jin, F, Jorgenson, E, Knowles, JA, Kohane, IS, Kraft, J, Kretzschmar, WW, Krogh, J, Kutalik, Z, Lane, JM, Li, Y, Li, Y, Lind, PA, Liu, X, Lu, L, MacIntyre, DJ, MacKinnon, DF, Maier, RM, Maier, W, Marchini, J, Mbarek, H, McGrath, P, McGuffin, P, Medland, SE, Mehta, D, Middeldorp, CM, Mihailov, E, Milaneschi, Y, Milani, L, Mill, J, Mondimore, FM, Montgomery, GW, Mostafavi, S, Mullins, N, Nauck, M, Ng, B, Nivard, MG, Nyholt, DR, O'Reilly, PF, Oskarsson, H, Owen, MJ, Painter, JN, Pedersen, CB, Pedersen, MG, Peterson, RE, Pettersson, E, Peyrot, WJ, Pistis, G, Posthuma, D, Purcell, SM, Quiroz, JA, Qvist, P, Rice, JP, Riley, BP, Rivera, M, Mirza, SS, Saxena, R, Schoevers, R, Schulte, EC, Shen, L, Shi, J, Shyn, SI, Sigurdsson, E, Sinnamon, GBC, Smit, JH, Smith, DJ, Stefansson, H, Steinberg, S, Stockmeier, CA, Streit, F, Strohmaier, J, Tansey, KE, Teismann, H, Teumer, A, Thompson, W, Thomson, PA, Thorgeirsson, TE, Tian, C, Traylor, M, Treutlein, J, Trubetskoy, V, Uitterlinden, AG, Umbricht, D, der Auwera, SV, van Hemert, AM, Viktorin, A, Visscher, PM, Wang, Y, Webb, BT, Weinsheimer, SM, Wellmann, J, Willemsen, G, Witt, SH, Wu, Y, Xi, HS, Yang, J, Zhang, F, Arolt, V, Baune, BT, Berger, K, Boomsma, DI, Cichon, S, Dannlowski, U, de Geus, ECJ, DePaulo, JR, Domenici, E, Domschke, K, Esko, T, Grabe, HJ, Hamilton, SP, Hayward, C, Heath, AC, Hinds, DA, Kendler, KS, Kloiber, S, Lewis, G, Li, QS, Lucae, S, Madden, PFA, Magnusson, PK, Martin, NG, McIntosh, AM, Metspalu, A, Mors, O, Mortensen, PB, Müller-Myhsok, B, Nordentoft, M, Nöthen, MM, O'Donovan, MC, Paciga, SA, Pedersen, NL, Penninx, BWJH, Perlis, RH, Porteous, DJ, Potash, JB, Preisig, M, Rietschel, M, Schaefer, C, Schulze, TG, Smoller, JW, Stefansson, K, Tiemeier, H, Uher, R, Völzke, H, Weissman, MM, Werge, T, Winslow, AR, Lewis, CM, Levinson, DF, Breen, G, Børglum, AD and Sullivan, PF (2018) Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nature Genetics 50, 668.CrossRefGoogle ScholarPubMed
Zayats, T, Athanasiu, L, Sonderby, I, Djurovic, S, Westlye, LT, Tamnes, CK, Fladby, T, Aase, H, Zeiner, P, Reichborn-Kjennerud, T, Knappskog, PM, Knudsen, GP, Andreassen, OA, Johansson, S and Haavik, J (2015) Genome-wide analysis of attention deficit hyperactivity disorder in Norway. PLOS ONE 10, e0122501.CrossRefGoogle ScholarPubMed
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The positive end of the polygenic score distribution for ADHD: a low risk or a protective factor?
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