Schizophrenia affects about 1 percent of the world population. We do not currently understand the biological underpinnings of schizophrenia well enough to design effective treatment strategies. Twin and adoption studies supported a genetic etiology. It is becoming clear that its inheritance is partitioned between the rare and common variants in hundreds of genes, each one having a small effect. The sample size required to elucidate the genetic etiology of schizophrenia can be achieved through large scale collaborative efforts, which are currently ongoing. A study published by Psychiatric Genomics Consortium in 2014 identified 108 Genome- Wide significant loci associated for the disorder in samples with European ancestry. Although it was an important milestone in schizophrenia genetics these loci only explain a small proportion of the genetic variance. Expansion of this approach in size, and to other population groups, is required to discovery of additional genetic variants associated with schizophrenia. We propose to ascertain and collect 10,000 cases and 10,000 controls from Pakistan. We have already ascertained and collected 2,000 cases and 1,000 controls. We have formed a consortium of Pakistani psychiatrists at 12 centers. These samples will be genotyped at Stanley Center for Psychiatric Research with Illumina Global Screening Array (GSA), which will contain a backbone of ~660,000 SNPs, which provides LD coverage and imputation accuracy of >0.8, for over 87% of the South Asian genome. There is a strong tradition of consanguineous marriages in Pakistan which has an advantage for genetic studies, especially of recessively inherited traits. We will analyze these data for common SNPs, haplotypes, and copy number variations (CNVs). In association analysis we will examine for recessive inheritance, in addition to additive models of common variants to disease. We will perform a homozygosity mapping to identify regions that are enriched for Runs of Homozygosity (ROH) in cases, as compared to controls. This population will have a different linkage disequilibrium structure which will help to narrow down the genomic intervals containing the potential causative variants at the 108 loci identified in the Caucasian Genome Wide Association Study. We will share these data with broader scientific community via the Psychiatric Genomics Consortium and dbGaP.

We will ascertain and genotype large cohort of Pakistani individuals with (n=8,000) and without (n=9,000) schizophrenia (SCZ). Added to our existing Pakistani samples, a total of 10,000 cases and 10,000 controls will be included in genome-wide association studies and these data will be contributed to the Psychiatric Genomics Consortium (PGC) and to the Database of Genotypes and Phenotypes (dbGaP). In Pakistan, consanguineous marriages are common and as a result we will be able to examine recessively inherited variants in addition to additive model of inheritance.