Jaanus Harro, MD, PhD, Professor, University of Tartu, Estonia
Bill Deakin, MD, PhD, Professor, University of Manchester, United Kingdom
In this dissertation, we have focused on the functional rs324981 A>T polymorphism of the gene NPSR1 (Asn107Ile) that encodes for the neuropeptide S (NPS) receptor and is a relatively newly identified research target. We have shown that NPSR1 is associated with the development of personality, hyperactivity, anxiety, depressiveness, self-esteem, suicidality, affective/anxiety disorders, alcohol use and alcohol use disorders, and sleep-related measures. We have also found profound NPSR1 genotype by sex interactions in general population.
In females, the probable lower NPS-ergic activity in the NPSR1 A-allele carriers, and especially in AA-homozygotes, bears a risk for affective and anxiety-related dysregulation already in adolescence. The risk for developing maladaptive traits is significantly higher in case of adverse family environment. As a consequence, females with the AA genotype had reported suicidal behaviour more frequently and had more often developed affective/anxiety disorders by age 25. Emotion dysregulation may also render them vulnerable to alcohol use, as some females carrying the A-allele develop AUD already in young adulthood.
In males, an impulsivity-related early-onset pathway to AUD was revealed to occur in T-allele carriers, and in particular in TT homozygotes: Already in adolescence, they exhibit more ADHD symptoms and impulsivity that could make them vulnerable to alcohol use, especially when experiencing adverse environment. So, many males carrying the T-allele develop AUD by young adulthood. Based on the longitudinal database, a delayed-onset pathway to AUD is also suggested for the AA genotype: the increase of adaptive impulsivity, extraversion and openness to experience by age 25 in males with AA genotype can make them vulnerable to higher alcohol use. However, future studies have to reveal whether AUD will develop in male AA subjects in later age.
NPSR is clearly a tempting target for drug development as it affects emotion regulation, arousal and alcohol abuse. Future research should address the apparently distinct pattern of emotion regulation by A- and T-allele carriers.