Genes in context

Abstract

Addictions are moderately heritable but influences of diverse genes are stronger on addiction-relevant brain functions modified by these genes, as illustrated by strong effects of functional variants in neuropeptide Y and COMT on brain stress and emotion responses as compared to their weak effects on complex behavior. Vulnerability to addiction is modified by stress and endocrine factors, and effects of several functional variants, for example MAOA, which is endocrine-modified, and FKPBP5, which is stress modified, are stronger in individuals who have received the exposure. Furthermore, rare and uncommon alleles are an elusive source of vulnerability. Discovery of these rare alleles and their actions has been hampered by weak contexts. To identify rare variants and tie them to behavior we applied deep sequencing in scenarios where effects of rare alleles are stronger. In Finns, a founder population with restricted medical genetic disease variation, we discovered a stop codon in the HTR2B serotonin receptor. It leads to uncompensated loss of function, can contribute to severe impulsivity and alcoholism, and is restricted to Finns in line with the founder characteristics of this population. The behavioral effects of loss of Htr2b function were validated in the Htr2b knockout mouse, a model organism with a uniform background of genotype and upbringing, and extended to the level of neural function, including the role of this receptor in regulating phasic dopamine release in the mesolimbic system. Via exome sequencing of the alcohol preferring (P) rat, one of the most widely accepted model organisms for alcoholism, we found a stop codon in the Grm2 metabotropic glutamate receptor gene. This stop codon was genetically fixed by selection in the P rat, leads to uncompensated effects on glutamate function, and – as shown by genetic and pharmacologic studies- is partially responsible for the increased alcohol preference in these rats.