Genetic variation associated with euphorigenic effects of d -amphetamine is associated with diminished risk for schizophrenia and attention deficit hyperactivity disorder

Abstract

Here, we extended our findings from a genome-wide association study of the euphoric response to d-amphetamine in healthy human volunteers by identifying enrichment between SNPs associated with response to d-amphetamine and SNPs associated with psychiatric disorders. We found that SNPs nominally associated (P ≤ 0.05 and P ≤ 0.01) with schizophrenia and attention deficit hyperactivity disorder were also nominally associated with d-amphetamine response. Furthermore, we found that the source of this enrichment was an excess of alleles that increased sensitivity to the euphoric effects of d-amphetamine and decreased susceptibility to schizophrenia and attention deficit hyperactivity disorder. In contrast, three negative control phenotypes (height, inflammatory bowel disease, and Parkinson disease) did not show this enrichment. Taken together, our results suggest that alleles identified using an acute challenge with a dopaminergic drug in healthy individuals can be used to identify alleles that confer risk for psychiatric disorders commonly treated with dopaminergic agonists and antagonists. More importantly, our results show the use of the enrichment approach as an alternative to stringent standards for genome-wide significance and suggest a relatively novel approach to the analysis of small cohorts in which intermediate phenotypes have been measured.G enome-wide association studies (GWAS) implicitly assume that all SNPs in the genome are equally likely to be causal, although most SNPs are unlikely to have any functional consequences. Studies from our groups and others have shown the use of incorporating prior information about SNPs into the genetic analysis of complex traits, including autism and bipolar disorder (1-6). These studies have shown that there is an enrichment of SNPs with functional consequences (e.g., expression quantitative trait loci) among SNPs modestly associated with a broad spectrum of complex traits.We recently conducted, to our knowledge, the first GWAS of an intermediate pharmacogenetic phenotype, namely the acute subjective response to a drug of abuse, d-amphetamine, in a sample of 381 healthy human volunteers (7). We identified only one genomewide significant association, and no replication samples were available; thus, the results were difficult to interpret. In the present study, we sought to further interrogate the numerous nominally significant associations from our d-amphetamine response GWAS. We hypothesized that nominally significant associations would be mostly false positives but also, would be enriched for true positives.Amphetamine produces its subjective and behavioral effects in part by increasing synaptic levels of dopamine (8). We took advantage of prior GWASs for psychiatric disorders to identify a subset of SNPs that showed nominal association with both amphetamine response and psychiatric disorders in which dopaminergic signaling is also hypothesized to play an important role. We predicted that, if these different phenotypes had shared susceptibility alleles, then we would ...

Genetics of attention deficit hyperactivity disorder

“…Similarly, prior reports of familial co-transmission of ADHD and depression [54] have been extended by showing shared SNP heritability between the two disorders [98]. Using a novel drug challenge paradigm, Hart et al [111] found that the polygenic scores for both schizophrenia and ADHD were associated with the euphoric response to amphetamine, which suggests that the genetic association between these disorders may be due to variants in the neural systems regulating the euphoric response to amphetamine.…”

Variants in WFS1 and Other Mendelian Deafness Genes Are Associated with Cisplatin-Associated Ototoxicity

“…SNPs in VAC14 associated with docetaxel-induced peripheral neuropathy (46), and the gene was recently shown to be mutated in pediatric-onset neurological disease (47). Beyond chemotherapy studies, genetic variants that associate with the euphoric effects of d -amphetamine significantly overlap with variants that decrease risk for schizophrenia and attention deficit hyperactivity disorder (48). The broad implication is that adverse drug events and related, non-drug-induced phenotypes may have related genetic etiologies, especially in the absence of large effects from genetic variation in enzymes involved in drug absorption, metabolism, distribution or excretion.…”

Genome-Wide Association Study of Loneliness Demonstrates a Role for Common Variation

“…It is widely accepted that humans have varying degrees of sensitivity to social isolation; however, the question of whether or not the genetic basis of this variability also underlies the risk for common psychiatric diseases remains largely unexplored. We have previously reported that genetic variation in the initial sensitivity to the euphoric effects of amphetamine is genetically correlated with the risk for both schizophrenia and ADHD (Hart et al, 2014). That provocative finding Table 4 Associations between Polygenic Scores for Neuroticism from SSGAC (Okbay et al, 2016) The testing set was an independent set using the data of HRS; the polygenic scores have been standardized, and hence the β coefficients from the Neuroticism linear regression model correspond to a 1 SD change in the polygenic score.…”