Investigating Direct and Indirect Genetic Effects in Attention-Deficit/Hyperactivity Disorder Using Parent-Offspring Trios |
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| Institution: | 1. MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom;2. Wolfson Centre for Young People’s Mental Health, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom;3. School of Psychology, Cardiff University, Cardiff, United Kingdom;4. Cwm Taf Morgannwg University Health Board, Wales, United Kingdom |
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| Abstract: | BackgroundAttention-deficit/hyperactivity disorder (ADHD) is highly heritable, but little is known about the relative effects of transmitted (i.e., direct) and nontransmitted (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 overtransmitted to ADHD probands. We also tested for indirect or genetic nurture effects by examining whether nontransmitted ADHD polygenic liability is elevated. Finally, we examined whether complete trios are representative of the clinical ADHD population.MethodsPolygenic risk scores (PRSs) for ADHD, anxiety, autism, bipolar disorder, depression, obsessive-compulsive disorder, schizophrenia, Tourette syndrome, and cognitive ability were calculated in UK control subjects (n = 5081), UK probands with ADHD (n = 857), their biological parents (n = 328 trios), and also a replication sample of 844 ADHD trios.ResultsADHD PRSs were overtransmitted and cognitive ability and obsessive-compulsive disorder PRSs were undertransmitted. These results were independently replicated. Overtransmission of polygenic liability was not observed for other disorders. Nontransmitted alleles were not enriched for ADHD liability compared with control subjects. 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.ConclusionsThe 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 nontransmitted neurodevelopmental/psychiatric parental alleles do not contribute indirectly to ADHD via genetic nurture. Furthermore, ascertainment of complete ADHD trios may be nonrandom, in terms of demographic and clinical factors. |
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| Keywords: | ADHD Case-control design Genetic nurture Missing data Polygenic risk scores Trio design |
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