Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection

Schizophrenia is a disorder that includes psychosis as well as negative symptoms such as social and emotional withdrawal. The onset of psychosis typically does not occur until late adolescence or early adulthood, but clinical and epidemiological studies do indicate that schizophrenia represents a disturbance of neurodevelopment. In addition, this disease is associated with substantial mortality and morbidity, with an average decrease in life expectancy of 15–30 years. “Recovery,” or “cure,” rarely happens, and, sadly, most patients continue to have poor social and functional outcomes.

Schizophrenia is both highly heritable and polygenic (involving many contributing genes, perhaps epigenetic effects also). Relative contributions of alleles (each gene has two alleles, one from each parent) of various frequencies are not anywhere near resolved –– but recent studies, captured by genome-wide association study (GWAS) arrays, can account for 35-45% of risk variance explained.

It is interesting to consider, from an evolutionary point-of-view, HOW (or WHY) these common risk alleles persist in the population. Various hypotheses have been proposed, including: [a] compensatory advantage (i.e. “balancing selection,” such as the sickle-cell trait recently discussed in these GEITP pages), whereby schizophrenia-associated alleles might confer a reproductive advantage; [b] hitch-hiking (risk-associated alleles are maintained by their linkage to “nearby” positively-selected alleles); and [c] contrasting theories that attribute these effects to rare variants and gene–environment interactions.

Authors [see attached article] describe a new GWAS of schizophrenia (11,260 cases; 24,542 controls), and, through meta-analysis with existing data, they identify 50 new, unique associated loci –– and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, authors identified candidate causal genes within 33 loci. They also discovered that the “common variant association signal” is highly enriched among genes that are under strong selective pressures. These data help us to understand the genetic architecture (“all things genetic” that contribute to the trait) of schizophrenia, highlight the importance of mutation-intolerant genes, and suggest a mechanism by which common-risk variants persist in the population.

This 2o18 study underscores comments made in a review 9 years ago [Nat Rev Genet 2oo9; 10: 134] [also attached] in which it was noted that “a meaningful proportion of disease risk appeared to be associated with ancestral alleles” (i.e. human alleles common to the great apes). More than two-thirds of the population-attributable risk single-nucleotide polymorphisms (parSNPs) –– that were listed on the National Human Genome Research Institute’s Catalog of Published GWAS (by the end of 2oo8) –– had already been remarked to correspond to the allele that is commonly observed in chimpanzees and macaques. Those findings imply that these “protective variants seen in humans” (e.g. such as those associated with increased risk of schizophrenia) have “been around (evolutionarily) for a long, long time.”

Nature Genet Mar 2o18; 50: 381–389

This entry was posted in Center for Environmental Genetics. Bookmark the permalink.