title: Indirect effect of corticotropin-releasing hormone receptor 1 gene variation on negative emotionality and alcohol use via right ventrolateral prefrontal cortex.
abstract: Variations in the corticotropin-releasing hormone receptor 1 (CRHR1) gene have been found to interact with stress in modulating excessive alcohol consumption. However, the neural mechanisms through which CRHR1 influences this risk in humans is largely unknown. This study examined the influence of an intronic CRHR1 gene variant, rs110402, on brain responses to negative emotional words, negative emotional traits, and alcohol use in adolescents and young adults at high risk for alcoholism. Childhood stress was investigated as a potential moderator. Using functional magnetic resonance imaging, we found that a region in the right ventrolateral prefrontal cortex (rVLPFC) was more engaged during negative emotional word processing in G homozygotes than in A allele carriers (p(FWE corrected) < 0.01, N = 77). Moreover, an indirect effect of genotype on negative emotionality via rVLPFC activation (p < 0.05, N = 69) was observed, which was further moderated by childhood stress (p < 0.05, N = 63). Specifically, with low childhood stress, G homozygotes exhibited lower levels of negative emotionality associated with greater rVLPFC activation, suggesting that the rVLPFC is involved in reappraisal that neutralizes negative emotional responses. In addition, we found that genotype indirectly modulated excessive alcohol consumption (p < 0.05, N = 69). Specifically, G homozygotes showed greater rVLPFC activation and had lower levels of negative emotionality, which were associated with fewer binge-drinking days and fewer alcohol related problems. This work provides support for a model in which CRHR1 gene variation modulates the risk of problem drinking via an internalizing/negative affect pathway involving rVLPFC and reappraisal of negative emotion.
authors.affiliation: Department of Psychiatry, Addiction Research Center, and Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Yi G
authors.initials: YG
authors.lastname: Glaser
authors.forename: Jon-Kar
authors.initials: JK
authors.lastname: Zubieta
authors.forename: David T
authors.initials: DT
authors.lastname: Hsu
authors.forename: Sandra
authors.initials: S
authors.lastname: Villafuerte
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Mickey
authors.forename: Elisa M
authors.initials: EM
authors.lastname: Trucco
authors.forename: Margit
authors.initials: M
authors.lastname: Burmeister
authors.forename: Robert A
authors.initials: RA
authors.lastname: Zucker
authors.forename: Mary M
authors.initials: MM
authors.lastname: Heitzeg
mesh_terms: D000293:Adolescent; D000428:Alcohol Drinking / Q000453:epidemiology / Q000235:genetics* / Q000523:psychology*; D004644:Emotions / Q000502:physiology*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008957:Models, Genetic; D009341:Negativism; D017397:Prefrontal Cortex / Q000502:physiology*; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics*; D012307:Risk Factors; D013315:Stress, Psychological / Q000453:epidemiology / Q000235:genetics / Q000523:psychology; D055815:Young Adult; D000099052:CRF Receptor, Type 1
chemical_list: D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1
keywords: CRHR1; alcohol consumption; childhood stress; genetics; negative emotionality; prefrontal cortex