Pathway-based Approaches for the Analysis of Psychiatric Disorder Genotypes
Zusammenfassung der Projektergebnisse
The genetic basis of psychiatric and neurodevelopmental disorders is complex and despite substantial genetic components in the disease risk identified in twin studies, the underlying biological mechanisms remain elusive. In recent years large-scale genetic mapping studies (genome-wide linkage and association studies) have identified a large number of potential risk loci. However, these loci only account for a small percentage of the observed heritability of these disorders. This “missing heritability“ is one of the central challenges of medical genetics today. The most commonly proposed disease model is a poly-genic mode of inheritance, in which many common and rare variants contribute to disease risk and shape the phenotypic presentation in each individual case. The unraveling of this genetic complexity is further complicated by the extreme phenotypic heterogeneity of these disorders, which typically manifest along a spectrum of severity and associated phenotypes. The overall objective of this project was to explore different strategies and methods to address the issue of missing heritability. This included careful analysis of sub-phenotypes and stratification to obtain more homogeneous samples, integrative analysis of genotype and whole genome sequence data to dissect the genetic complexity, gene set enrichment analysis to assess convergence of candidate variants to known biological pathways and development of novel gene sets to test specific hypothesis about the underlying disease model. There were three main studies undertaken within the bounds of the project. The first study was a combination of sub-phenotype analysis and genome-wide association analysis of sex-specific genetic risk factors and phenotypic differences in Autism Spectrum Disorder (ASD). The analysis revealed phenotypic differences between male and female ASD cases as well as potential sex-specific genetic risk factors. Our results demonstrate stratification as a useful strategy for addressing heterogeneity in ASD and complex genetic disease in general. The second study was focused on the dissection of genetic complexity underlying bipolar disorder in an extended pedigree of ~500 Old Order Amish subjects. Here, we integrated genotype and whole genome sequence data to identify genetic risk factors and candidate regions for bipolar susceptibility and subsequent analysis by pathway-based methods. Our study demonstrates the underlying complexity and heterogeneity of bipolar disorder even in this genetic isolate and has profound implications for the study of bipolar disorder and other complex diseases in general populations. In the third study we made use of experimental findings (phenotypes) in mutant mice and sequencing data of human genomes, to establish a set of ~2,5K putative essential human genes. This study is the first to jointly consider deep sequencing data from human populations in conjunction with rich phenotypic resources from model systems to identify genes that are likely essential. The creation of a catalog of essential genes has critically important implications for clinical sequencing studies for human disease.
