PROJECT SUMMARY Schizophrenia is a heritable psychiatric disease affecting approximately 1% of the population. The disease is associated with high morbidity and mortality and is a leading cause of disability. Genomewide association studies (GWAS) have identified >100 genetic loci associated with schizophrenia. However standard GWAS are largely limited to detecting simple point mutations, or single nucleotide polymorphisms (SNPs), consisting of single base pair substitutions. Thus, GWAS is unable to capture complex variants such as copy number variants (CNVs) and tandem repeats (TRs) that are not well tagged by SNPs. Multiple lines of evidence support the hypothesis that TRs play a role in psychiatric disease. TRs are one of the largest sources of genetic variation, are weakly tagged by SNPs, and play a significant role in regulating gene expression and splicing. Intriguingly, >30 Mendelian disorders are caused by TR expansions. Nearly all repeat disorders involve neurological phenotypes, many have psychiatric components, and some implicated genes have also been identified in schizophrenia GWAS. I hypothesize that tandem repeats play a significant role in schizophrenia risk and drive a subset of GWAS signals. I propose to develop an array of computational techniques to integrate TRs into psychiatric and other GWAS. In Aim 1 we will develop algorithms to accurately genotype long TR polymorphisms in large nextgeneration sequencing cohorts. In Aim 2 we will generate a high quality reference haplotype panel for a targeted set of TRs using traditional familybased phasing methods combined with long range phasing from novel singlemolecule sequencing technologies. In Aim 3 we will deeply characterize medically relevant TRs in psychiatric disease by imputing TRs into large existing GWAS cohorts. Finally, in Aim 4 we will develop a novel haplotype test capturing genomewide TR associations from existing GWAS datasets. Taken together, these innovations will provide a powerful framework for interrogating the role of TRs in human disease. Genomewide scans for association (Aim 4) can be combined with targeted methods of Aims 13 for genotyping or imputing TRs, fine mapping against other variant types, and performing functional follow up. Technologies for high throughput TR genotyping and imputation will revolutionize our ability to discover diseaseassociated TRs and enable unprecedented study of TRs in broad applications including GWAS, Mendelian genetics, and cancer.