BIRS Workshop Lecture Videos
The links between DNA variation and complex traits Li, Yang
A central goal of genetics is to understand the links between genetic variation and disease. Intuitively, one might expect disease risk to be explained by a small number of disease-causing variants that cluster in or near core genes and pathways. However recent GWASs have revealed that most complex traits, including height and schizophrenia risk, are highly polygenic. While the strongest of these associations sometimes map to genes directly linked to the trait, the majority of association signals are found across much of the genome, including near genes with housekeeping-like functions. For example, we found that over half of the genomic SNPs are in high linkage disequilibrium with a SNP that has an estimated effect of increasing height by an average of 0.145mm. To better understand how these widespread signals contribute to complex traits, we focused on three diseases for which causal cell-types are relatively well defined: schizophrenia, Crohn’s disease, and rheumatoid arthritis. Again, we found that association signals were widely dispersed. We further found that the causal signal was present sometimes exclusively in regions marked by active chromatin in the relevant cell types (45% to ~100%), but vastly depleted or absent from regions that are generally inactive across cell-types. While variation in cell type-specific gene networks contributes to complex disease risk, we show evidence that genes with housekeeping-like functions cumulatively account for a greater fraction of total SNP heritability. As expected, we found that relevant gene sets exhibited the greatest enrichment in trait heritability. However, we also observed a strong linear relationship between the size of the gene sets and the proportion of heritability they explained, further supporting the hypothesis that most if not all transcribed genes in the relevant cell-type(s) contribute to disease risk. Together, these findings imply a need for rethinking models of complex traits. We propose that gene regulatory networks are sufficiently interconnected for all genes expressed in disease-relevant cells to be liable to affect the functions of core disease-related genes. Consequently, the bulk of the genetic effects on disease are mediated through genes without any direct relationship to disease function, and variation in non-disease genes previously thought to be innocuous may in fact drive complex disease risk in human populations.
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