Inferring schizophrenia biology from genome-­wide data

Disease loci underlying complex disorders such as schizophrenia(SCZ)are likely to exist as variants of multiple typesbeyond the single nucleotide polymorphisms(SNPs) typically surveyed in genome-­‐wide association studies(GWAS). Large copy number variants (CNV), small insertions and deletions (INDELS),rare compound heterozygous mutations and other classes of genetic variation are all expected to contribute to disease risk. A true understanding of disease genetics cannot be attained without careful consideration of each class of variation and how they are related. Additionally, it is often the case that no or few single variants have strong enough effect sizes to attain the level of statistical significance required to offset the large number of tests performed in a genome-­‐wide single locus survey of any variant type. It has been shown that a cumulative burden of risk alleles is correlated with disease risk, indicating true biological signal within those variants. However, this approach merely implicates that class of variation across the genome and does not refine variants to a subset of risk regions or genes. Defining sets of genes within biological pathways and testing them as a group will allow for both the power of aggregating loci of small effect and interpretation of the underlying biology. This dissertation assesses the role of multiple classes of variation from different technologies in risk to schizophrenia with a particular focus on brain related biological pathways

Family-based genetic risk prediction of multifactorial disease

Genome-wide association studies have detected dozens of variants underlying complex diseases, although it is uncertain how often these discoveries will translate into clinically useful predictors. Here, to improve genetic risk prediction, we consider including phenotypic and genotypic information from related individuals. We develop and evaluate a family-based liability-threshold prediction model and apply it to a simulation of known Crohn's disease risk variants. We show that genotypes of a relative of known phenotype can be informative for an individual's disease risk, over and above the same locus genotyped in the individual. This approach can lead to better-calibrated estimates of disease risk, although the overall benefit for prediction is typically only very modest

Dissecting the shared genetic architecture of suicide attempt, psychiatric disorders, and known risk factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders

Revealing Complex Traits with Small Molecules and Naturally Recombinant Yeast Strains

SummaryHere we demonstrate that natural variants of the yeast Saccharomyces cerevisiae are a model system for the systematic study of complex traits, specifically the response to small molecules. As a complement to artificial knockout collections of S. cerevisiae widely used to study individual gene function, we used 314- and 1932-member libraries of mutant strains generated by meiotic recombination to study the cumulative, quantitative effects of natural mutations on phenotypes induced by 23 small-molecule perturbagens (SMPs). This approach reveals synthetic lethality between SMPs, and genetic mapping studies confirm the involvement of multiple quantitative trait loci in the response to two SMPs that affect respiratory processes. The systematic combination of natural variants of yeast and small molecules that modulate evolutionarily conserved cellular processes can enable a better understanding of the general features of complex traits

Telomere Length as a Quantitative Trait: Genome-Wide Survey and Genetic Mapping of Telomere Length-Control Genes in Yeast

Telomere length-variation in deletion strains of Saccharomyces cerevisiae was used to identify genes and pathways that regulate telomere length. We found 72 genes that when deleted confer short telomeres, and 80 genes that confer long telomeres relative to those of wild-type yeast. Among identified genes, 88 have not been previously implicated in telomere length control. Genes that regulate telomere length span a variety of functions that can be broadly separated into telomerase-dependent and telomerase-independent pathways. We also found 39 genes that have an important role in telomere maintenance or cell proliferation in the absence of telomerase, including genes that participate in deoxyribonucleotide biosynthesis, sister chromatid cohesion, and vacuolar protein sorting. Given the large number of loci identified, we investigated telomere lengths in 13 wild yeast strains and found substantial natural variation in telomere length among the isolates. Furthermore, we crossed a wild isolate to a laboratory strain and analyzed telomere length in 122 progeny. Genome-wide linkage analysis among these segregants revealed two loci that account for 30%–35% of telomere length-variation between the strains. These findings support a general model of telomere length-variation in outbred populations that results from polymorphisms at a large number of loci. Furthermore, our results laid the foundation for studying genetic determinants of telomere length-variation and their roles in human disease

Cis-Acting Regulation of Brain-Specific ANK3 Gene Expression by a Genetic Variant Associated with Bipolar Disorder

Several genome-wide association studies (GWAS) for bipolar disorder (BD) have found a strong association of the Ankyrin3 (ANK3) gene. This association spans numerous linked single nucleotide polymorphisms (SNPs) in a ~250 kb genomic region overlapping ANK3. The associated region encompasses predicted regulatory elements as well as two of six validated alternative first exons, which encode distinct protein domains at the N-terminus of the protein also known as ankyrin-G (AnkG). Using RNA Ligase-Mediated Rapid Amplification of cDNA Ends (RLM-RACE) to identify novel transcripts in conjunction with a highly sensitive, exon-specific multiplexed mRNA expression assay, we detected differential regulation of distinct ANK3 transcription start sites (TSSs) and coupling of specific 5’ ends with 3’ mRNA splicing events in post-mortem human brain and human stem cell-derived neural progenitors and neurons. Furthermore, allelic variation at the BD–associated SNP rs1938526 correlated with a significant difference in cerebellar expression of a brain-specific ANK3 transcript. These findings suggest a brain-specific cis-regulatory transcriptional effect of ANK3 may be relevant to BD pathophysiology

Polygenic overlap between schizophrenia risk and antipsychotic response: a genomic medicine approach

Therapeutic treatments for schizophrenia do not alleviate symptoms for all patients and efficacy is limited by common, often severe, side-effects. Genetic studies of disease can identify novel drug targets, and drugs for which the mechanism has direct genetic support have increased likelihood of clinical success. Large-scale genetic studies of schizophrenia have increased the number of genes and gene sets associated with risk. We aimed to examine the overlap between schizophrenia risk loci and gene targets of a comprehensive set of medications to potentially inform and improve treatment of schizophrenia