Integrative genomic analyses of consanguineous pedigrees aggregated with psychotic, affective and pervasive developmental disorders from Pakistan

Pakistan has the highest rate of consanguineous marriage in the world due to historical, religious, cultural, and social reasons. A long history of such intra-community 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 genome-wide and genetic disease profiles, especially for more common diseases, for such special genetic isolates remains largely under-investigated. Schizophrenia (SCZ), schizoaffective (SAF) and bipolar (BP) disorders are common brain diseases in all populations with largely unknown aetiology and molecular pathogenesis pathways. To date, the genetic architecture of these three main psychiatric disorders in such isolated consanguineous populations remains largely unknown. We’ve been investigating more than 10 large pedigrees aggregated with major mental disorders (with 10-30 affected individuals), generated genome-wise SNP genotyping data (300 samples) and whole exome sequencing data (243 samples). We’ve found several loci with common variants, and many genes with rare variants, which either showed marginal association with the disease phenotype, or demonstrated some population/pedigree specific variants that could contribute to the disease phenotype or other related traits. However, most of our results need to be further validated in a large sample size, particularly in a larger pool of population controls.