The Interplay Between Risky Sexual Behaviors and Alcohol Dependence: Genome-Wide Association and Neuroimaging Support for LHPP as a Risk Gene

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.