Pakistan Study of Causes of Depression (PASCAD)

Depression represents one of the biggest challenges to human health to date. It affects an estimated 300 million people, 4.4% of the world’s population1. Depression has been linked to a wide range of adverse health outcomes including cardiovascular disease, asthma, cancer, poor maternal and child health, substance abuse, and suicide and affects family relationships and work performance. Consequently, the burden of this common disorder and the implicated economic costs are immense. Depression represents the leading cause of health-related disabilities. More than 80% of this burden pertains to low- and middle-income countries (LMICs).

As part of this study, we are inviting individuals suffering from Depression to participate. Individuals who do not have any personal or family history of this disorder also are invited to participate. Further, the relatives of individuals with and without illness may be invited to participate, if they wish. In this research, we will study large groups of unrelated individuals with and without these disorders to identify any differences in their genes.

We may also compare the genes of affected and unaffected family members. We hope to find differences that may be associated with an increased risk of developing Depression and other mental and physical illnesses, conditions, or traits that affect disease course. In this study, Nearly 12,000 individuals will be enrolled in the next several years. This large number of research volunteers is necessary to identify the exact genetic factors that may play a role in disease.

As the genetic findings have accumulated, it is apparent that they aggregate in neurologically meaningful molecular complexes, such as the L-type calcium channel, postsynaptic glutamate/NMDA receptors, and postsynaptic density; this indicates the increasing power of such analyses to implicate specific biological pathways and molecular complexes. These insights from common variants are in turn strengthening studies of rare variation in schizophrenia: although rare-variant studies remain under-powered to discover effects of individual genes in unbiased genome-wide searches, rare and de novo gene-disruptive variants in genes encoding the subunits of these same complexes are (as a group) substantially more common in affected than unaffected individuals. A clear lesson from the trajectory of gene discovery by the PGC involves the critical importance of sample size for gene discovery in polygenic illness, in which heritability is distributed across large numbers of loci. The PGC’s current work draws upon data from individuals with European ancestry (EA) in the form of a meta-analysis of 52 cohorts. There is a growing recognition within the scientific community that the GWAS effort needs to expand to populations with non-European ancestry. The Pakistani population, with its unique characteristics of high consanguinity, is particularly suitable for the discovery, and subsequent study, of pathological loci for schizophrenia that act in either a recessive or additive manner. The analysis of Pakistani genomes thus presents an important scientific opportunity to enlarge and deepen our understanding of the genetic predisposition to schizophrenia, as well as a chance to make sure that research is inclusive of recessively transmitted variants, that are usually of higher penetrance.