Testing for the mediating role of endophenotypes using molecular genetic data in a twin study of ADHD traits

Abstract

Family and twin studies have identified endophenotypes that capture familial and genetic risk in attention‐deficit/hyperactivity disorder (ADHD), but it remains unclear if they lie on the causal pathway. Here, we illustrate a stepwise approach to identifying intermediate phenotypes. First, we use previous quantitative genetic findings to delineate the expected pattern of genetically correlated phenotypes. Second, we identify overlapping genetic associations with ADHD‐related quantitative traits. Finally, we test for the mediating role of associated endophenotypes. We applied this approach to a sample of 1,312 twins aged 7–10. Based on previous twin model‐fitting analyses, we selected hyperactivity–impulsivity, inattention, reading difficulties (RD), reaction time variability (RTV) and commission errors (CE), and tested for association with selected ADHD risk alleles. For nominally significant associations with both a symptom and a cognitive variable, matching the expected pattern based on previous genetic correlations, we performed mediation analysis to distinguish pleiotropic from mediating effects. The strongest association was observed for the rs7984966 SNP in the serotonin receptor gene (HTR2A), and RTV (P = 0.007; unadjusted for multiple testing). Mediation analysis suggested that CE (38%) and RTV (44%) substantially mediated the association between inattention and the T‐allele of SNP rs3785157 in the norepinephrine transporter gene (SLC6A2) and the T‐allele of SNP rs7984966 in HTR2A, respectively. The SNPs tag risk‐haplotypes but are not thought to be functionally significant. While these exploratory findings are preliminary, requiring replication, this study demonstrates the value of this approach that can be adapted to the investigation of multiple genetic markers and polygenic risk scores. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

PHDA: Afinal, qual a sua origem? Uma revisão dos fatores etiológicos

“…Embora estes estudos não tenham identificado genes específicos da PHDA em níveis de associações genómicas com significância (Neale et al, 2010), resultados auspiciosos emergiram a partir de estudos de genes candidatos à PHDA envolvendo os sistemas dos neurotransmissores da monoamina (Gizer et al, 2009). Os dados mais robustos apontam para variações nos genes recetores D4 e D5 da dopamina; outros genes que mostram possíveis associações com a PHDA incluem o SLC6A4 (que codifica o transportador de serotonina dependente do sódio), o SLC6A2 (gene transportador da norepinefrina e o alelo T do rs7984966), o HTR1B (que codifica o recetor de serotonina 1B), o HTR2A [polimorfismo de nucleótido único (SNP -single nucleotide polymorphism) rs7984966 no gene recetor da serótina] e o SNAP25 (que codifica a proteína associada a sinaptossomas) (Asherson & Gurling, 2011;Gizer et al, 2009;Pinto, Asherson, Ilott, Cheung, & Kuntsi, 2016).…”

Family, twin, and adoption studies of childhood onset psychiatric and neurodevelopmental disorders

“…Future work might further clarify the role of “internalizing” symptoms by reporting on self‐rated measured in children and adolescents, as well as adults. Pinto et al [] investigated the association of tics, ADHD, and obsessive‐compulsive symptoms. They concluded that the association between tics and obsession symptoms, and to a lesser extent ADHD, was in parent explained by a shared genetic factor, but the greatest proportion of variance was explained by specific non‐shared environmental influences, and the they could not be considered as alternative expressions of the same underlying genetic aetiology.…”

“…Finally, this special issue illustrates how information from family, twin, and adoption studies can be used to inform the use of high‐tech, in‐depth assessments of neurobiological function, and molecular genetic variation [Pinto et al, ]. The goal is to identify neurobiological substrates that play a direct causal role, underpinning the aetiological pathway from genetic risks to changes in brain function to neurodevelopmental phenotypes.…”

“…The goal is to identify neurobiological substrates that play a direct causal role, underpinning the aetiological pathway from genetic risks to changes in brain function to neurodevelopmental phenotypes. Pinto et al [] advocate a three‐step procedure. First, to identify behavioral and neurobiological/neural/cognitive phenotypes that is genetically correlated (so called endophenotypes).…”

“…This last step is essential to the distinction between pleiotropic effects and direct causal, or mediating effects of the endophenotype on the pathway from genes to behavior. The Pinto et al [] study is limited by its focus on candidate gene associations since the effects of individual genetic variants explain only a very tiny proportion of phenotypic variance. However, in future we expect to see this approach applied more widely using polygenic risks obtained from very large discovery sets.…”