title: The Interplay Between Risky Sexual Behaviors and Alcohol Dependence: Genome-Wide Association and Neuroimaging Support for LHPP as a Risk Gene.
abstract: To identify genetic mechanisms involved in the interplay of risky sexual behaviors (RSBs) and alcohol dependence (AD), we conducted genome-wide gene-by-AD (GW-GxAD) analyses of RSB in 3924 alcohol-exposed and sexually experienced subjects. RSBs were defined as a score based on lifetime experiences of unprotected sex and multiple sexual partners. Diagnosis of lifetime AD was defined by DSM-IV criteria. To follow-up the genetic findings, functional magnetic resonance imaging analyses were conducted in an independent sample. A trans-population genome-wide significant signal was identified in LHPP (rs34997829; z=-5.573, p=2.51 × 10-8) in the GxAD analysis that also showed associations in the AD-stratified association analysis (AD z=-2.032 and non-AD z=4.903). The clinical relevance of the result was confirmed by the significant interaction between LHPP rs34997829 and AD with respect to self-reported sexually transmitted disease (STD; z=-2.809, p=4.97 × 10-3). The neuroimaging follow-up analysis of LHPP rs34997829 showed reduced power of the left superior frontal gyrus (t=-3.386, p=9.56 × 10-4) and increased power at the right amygdala (t=3.287, p=1.33 × 10-3) in the resting amplitude of low frequency fluctuations analysis; and reduced activation of the anterior cingulate region (t=-2.961, p=3.69 × 10-3) in the monetary incentive delay task. In conclusion, LHPP locus is associated to AD-RSB interaction; and with brain circuitries previously implicated in the inhibition of risky behavior and impulsiveness, emotional regulation, and impulse control/error monitoring. Thus, LHPP is a strong candidate to influence RSB and STD risk in the context of AD.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine and VA CT Healthcare Center, West Haven, CT, USA.
authors.forename: Renato
authors.initials: R
authors.lastname: Polimanti
authors.affiliation: Department of Psychiatry, Yale University School of Medicine and VA CT Healthcare Center, West Haven, CT, USA.|Department of Biostatistics, Yale University School of Public Health, New Haven, CT, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Olin Neuropsychiatric Research Center, Institute of Living/Hartford Hospital, Hartford, CT, USA.
authors.forename: Shashwath A
authors.initials: SA
authors.lastname: Meda
authors.affiliation: Olin Neuropsychiatric Research Center, Institute of Living/Hartford Hospital, Hartford, CT, USA.
authors.forename: Krishna T
authors.initials: KT
authors.lastname: Patel
authors.affiliation: Department of Psychiatry, Yale University School of Medicine and VA CT Healthcare Center, West Haven, CT, USA.|Olin Neuropsychiatric Research Center, Institute of Living/Hartford Hospital, Hartford, CT, USA.|Department of Neurobiology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Godfrey D
authors.initials: GD
authors.lastname: Pearlson
authors.affiliation: Department of Biostatistics, Yale University School of Public Health, New Haven, CT, USA.|Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Departments of Medicine (Biomedical Genetics), Neurology, Ophthalmology, Biostatistics, and Epidemiology, Boston University Schools of Medicine and Public Health, Boston, MA, USA.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.affiliation: Department of Psychiatry, University of Pennsylvania School of Medicine and VISN 4 MIRECC, Philadelphia VAMC, Philadelphia, PA, USA.
authors.forename: Henry R
authors.initials: HR
authors.lastname: Kranzler
authors.affiliation: Department of Psychiatry, Yale University School of Medicine and VA CT Healthcare Center, West Haven, CT, USA.|Department of Neurobiology, Yale University School of Medicine, New Haven, CT, USA.|Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Gelernter
mesh_terms: D000328:Adult; D000437:Alcoholism / Q000235:genetics*; D000679:Amygdala / Q000000981:diagnostic imaging*; D005260:Female; D055106:Genome-Wide Association Study; D006179:Gyrus Cinguli / Q000000981:diagnostic imaging*; D006801:Humans; D043564:Inorganic Pyrophosphatase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging*; D012309:Risk-Taking; D012725:Sexual Behavior / Q000502:physiology*
chemical_list: D043564:Inorganic Pyrophosphatase; C543154:phospholysine phosphohistidine inorganic pyrophosphate phosphatase, human