Genetic effects of tissue-specific enhancers in schizophrenia and hypertrophic cardiomyopathy

Abstract

Most human conditions develop in genetically susceptible individuals from the interaction with environmental risk factors. These complex disorders result from the summation of effects from multiple genetic risk loci. Genome-wide association studies (GWASes) measure the association of single nucleotide polymorphisms (SNPs) with traits or conditions, and allow the creation of individualised polygenic risk scores. However, these explain only a small portion of a condition’s genetic heritability. Further, there is evidence that schizophrenia GWAS signals are enriched within genomic regulatory blocks, which are clusters of conserved non-coding elements that span key developmental loci and function as long-range enhancers activating transcription of target developmental genes. This suggests that enhancer-based annotations might be useful to refine polygenic signals for schizophrenia.

In this work, I aimed to increase the amount of variance explained by PRS for schizophrenia, and a comparison condition hypertrophic cardiomyopathy, using tissue-specific regulatory enhancer-promoter annotations. To do so, I developed neural- and cardiac-specific enhancer lists, which I tested for enrichment, respectively, in schizophrenia and hypertrophic cardiomyopathy (HCM) heritability. I found that neural-specific enhancers are highly enriched in schizophrenia heritability -- especially when overlapping genomic regulatory blocks. Then I created partitioned polygenic risk scores for enhancer-based and non-enhancer-based SNPs, where enhancer-based SNPs are prioritised. I further compared the amount of adjusted heritability for both conditions explained by original GWAS vs partitioned polygenic risk scores, and found up to a 6.5% increase in the Coefficient of Determination for schizophrenia, and similar amounts for HCM -- however, this was not statistically significant. The increasing trend was specific for brain-expressed enhancers in schizophrenia, while it was widespread for HCM. Finally, I considered whether neural-specific enhancer-based partitions might be better modelled in GWAS using nonadditive effects, however my results were inconclusive due to small sample sizes.