Grant: Operating Grant

Pakistan has the highest rate of consanguineous marriage in the world due to historical, religious, cultural and social reasons. A long history of such intracommunity and/or consanguineous marriage has divided the Pakistani population into many rural isolated clans, segregated by geography, language, religion and tribal group, and creating genetic isolates with individual mutation profiles. Consanguineous pedigrees have been successfully used in mapping rare recessive Mendelian disorders in the past. However, the potential influence of such long standing endogamous and consanguineous unions on overall levels of homozygosity genomewide and genetic disease profiles, especially for more common diseases, for such particular genetic isolates remains largely underinvestigated. Schizophrenia (SCZ), schizoaffective (SAF) and bipolar (BP) disorders are common brain diseases in all populations with largely unknown etiology and molecular pathogenesis pathways. Genetic factors have been considered important contributing causes and have been the focus of intensive research efforts in the past decades. To date, the genetic architecture of these three main psychiatric disorders remain largely unknown and very few convincing genetic factors have been identified. We propose to launch a thorough genomewide genetic investigation of 10 collected and clinically well characterized large consanguineous pedigrees from Pakistan to identify causative genetic variants contributing to these major mental disorders. The study of such isolated consanguineous populations with major psychiatric disorders offers a unique opportunity to identify transmitted mutations contributing to SCZ etiology. Thorough genetic and genomic investigations in these pedigrees will also help us better understand the effect of long-term endogamous/consanguineous marriage on the genetic profile and structure of such populations, particularly for complex genetic traits like SCZ.