Single nucleotide polymorphisms in the REG‐CTNNA2 region of chromosome 2 and NEIL3 associated with impulsivity in a Native American sample

Abstract

Impulsivity is a multi-faceted construct that, while characterized by a set of correlated dimensions, is centered around a core definition that involves acting suddenly in an unplanned manner without consideration for the consequences of such behavior. Several psychiatric disorders include impulsivity as a criterion, and thus it has been suggested that it may link a number of different behavioral disorders, including substance abuse. Native Americans experience some of the highest rates of substance abuse of all US ethnic groups. The described analyses used data from a low coverage whole genome sequence scan to conduct a genome-wide association study of an impulsivity phenotype in an American Indian community sample (n=658). Demographic and clinical information were obtained using a semi-structured interview. Impulsivity was assessed using a scale derived from the Maudsley personality inventory that combines both novelty-seeking and lack of planning items. The impulsivity score was tested for association with each variant adjusted for demographic variables, and corrected for ancestry and kinship, using EMMAX. Simulations were conducted to calculate empirical p-values. Genome-wide significant findings were observed for a variant 50 kb upstream from catenin cadherin-associated protein, alpha 2 (CTNNA2), a neuronal specific catenin, in the REG gene cluster. A meta-analysis of genome-wide association studies had previously identified common variants in CTNNA2 as being associated with excitement seeking. A second locus upstream of NEIL3 on chromosome 4 also achieved genome-wide significance. The association between sequence variants in these regions suggests their potential roles in the genetic regulation of this phenotype in this population.

Infant Inhibited Temperament in Primates Predicts Adult Behavior, is Heritable, and is Associated with Anxiety-Relevant Genetic Variation

“…Our preliminary genome-wide association analyses revealed a promising hit near the CTNNA2 gene in chromosome 13, which encodes Catenin alpha-2. This is of particular interest because CTNNA2 has been previously implicated in human association studies, including a GWGAS of anxiety disorders, and encodes a neuron-specific catenin that is important for cellto-cell adhesion and synaptic plasticity, is expressed throughout cortical and subcortical structures, and is implicated in numerous studies of IT-related phenotypes (17, [66][67][68][69][70][71][72][73]. The association analysis presented here does not constitute evidence for a definitive association between CTNNA2 and infant IT in the rhesus monkey.…”

“…Most excitingly Levey et al, (2019)(17) found SNPs in human CTNNA2 to be associated with anxiety disorders in their GWGAS (1/31 genes tested above). Consistent with a shared genetic substrate between anxiety, depression, and addiction, GWAS studies in humans have also implicated variation in the CTNNA2 gene in impulsivity (67), excitement seeking (68), depression with comorbid substance abuse (69), substance dependence (70), anorexia(71), and chronic pain (72). As noted in the main manuscript, the association analysis presented here does not constitute evidence for a definitive association between CTNNA2 and infant IT in the rhesus monkey.…”

Catenin Alpha 2 May Be a Biomarker or Potential Drug Target in Psychiatric Disorders with Perseverative Negative Thinking

“…For every outcome variable, the type I error rate was set to a two-sided 0.05, and the minor allele frequency (MAF) range was hypothesized between 0.01 and 0.5 by 0.01. Based on previous studies, the effect size was expected to be β = 0.08 [ 9 ] or β = 1.62 [ 7 ] in an additive model, for every variable. The range of potential MAF values and the two hypothesized effect sizes resulted in a range of statistical power values to detect the CTNNA2 SNP effects.…”

“…It has been implicated in bipolar disorder [ 2 ], adult attention-deficit/hyperactivity disorder (ADHD) [ 3 ], alcoholism [ 4 ], schizophrenia, and general cognitive function [ 5 ], as well as in success in smoking cessation [ 6 ]. Moreover, it has shown associations with personality traits and endophenotypes that lie on possible pathways between genes and disorders, namely: impulsivity, which covers both novelty seeking and lack of planning [ 7 ], as well as a common visual endophenotype of schizophrenia and autism spectrum disorder, namely deficits in sensitivity to visual stimuli of a low spatial and high temporal frequency [ 8 ].…”

Attempting to disentangle the relationship between impulsivity and longitudinal self-harm: Epidemiological analysis of UK household survey data

“…Recent evidence suggests that impulsivity questionnaires such as the UPPS-P are likely to be consistent across ethnicities (Stevens, Blanchard, Shi, & Littlefield, 2018). The role of genetics in potential impulsivity phenotypes within and between ethnicities has recently been examined in substance misuse (Ehlers et al, 2016), and risk-taking behaviour (Strawbridge et al, 2018). Strawbridge and colleagues in particular found that there were greater differences between sexes than between ethnicities in terms of the potential role of genetics on risk-taking behaviour.…”