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Investigating direct and indirect genetic effects in attention-deficit/hyperactivity disorder using parent-offspring trios

Martin, Joanna, Wray, Matthew, Agha, Sharifah Shameem, Lewis, Katie J. S., Anney, Richard, O'Donovan, Michael, Thapar, Anita and Langley, Kate 2022. Investigating direct and indirect genetic effects in attention-deficit/hyperactivity disorder using parent-offspring trios. Biological Psychiatry 10.1016/j.biopsych.2022.06.008

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Background Attention deficit hyperactivity disorder (ADHD) is highly heritable, but little is known about the relative effects of transmitted (i.e. direct) and non-transmitted (i.e. indirect) common variant risks. Using parent-offspring trios, we tested whether polygenic liability for neurodevelopmental and psychiatric disorders and lower cognitive ability is over-transmitted to ADHD probands. We also tested for indirect or ‘genetic nurture’ effects, by examining whether non-transmitted ADHD polygenic liability is elevated. Finally, we examined whether complete trios are representative of the clinical ADHD population. Methods Polygenic risk scores (PRS) for ADHD, anxiety, autism, bipolar disorder, depression, obsessive-compulsive disorder (OCD), schizophrenia, Tourette’s syndrome, and cognitive ability were calculated in UK controls (N=5,081), UK probands with ADHD (N=857), their biological parents (N=328 trios), and also a replication sample of 844 ADHD trios. Results ADHD PRS were over-transmitted and cognitive ability and OCD PRS were under-transmitted. These results were independently replicated. Over-transmission of polygenic liability was not observed for other disorders. Non-transmitted alleles were not enriched for ADHD liability compared to controls. Probands from incomplete trios had more hyperactive-impulsive and conduct disorder symptoms, lower IQ, and lower socioeconomic status than complete trios. PRS did not vary by trio status. Conclusions The results support direct transmission of polygenic liability for ADHD and cognitive ability from parents to offspring, but not for other neurodevelopmental/psychiatric disorders. They also suggest that non-transmitted neurodevelopmental/psychiatric parental alleles do not contribute indirectly to ADHD via genetic nurture. Furthermore, ascertainment of complete ADHD trios may be non-random, in terms of demographic and clinical factors.

Item Type: Article
Date Type: Published Online
Status: In Press
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information: This is an open access article under the terms of the CC-BY license.
Publisher: Elsevier
ISSN: 0006-3223
Date of First Compliant Deposit: 14 June 2022
Date of Acceptance: 6 June 2022
Last Modified: 31 Aug 2022 07:51

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