Abstract Bipolar disorder (BD) is a mental disorder characterized by alternating periods of depression and mania. Individuals with BD have higher levels of early mortality than the general population, and a substantial proportion of this may be due to increased risk for comorbid diseases. Recent evidence suggests that pleiotropy, either in the form of a single risk-allele or the combination of multiple loci genome-wide, may underlie medical comorbidity between traits and diseases. To identify the molecular events that underlie BD and related medical comorbidities, we generated imputed whole genome sequence (WGS) data using a population specific reference panel, for an extended multigenerational Old Order Amish pedigree (400 family members) segregating BD and related disorders. First, we investigated all putative disease-causing variants at known Mendelian disease loci present in this pedigree. Second, we performed genomic profiling using polygenic risk scores to establish each individual's risk for several complex diseases. To explore the contribution of disease genes to BD we performed gene-based and variant-based association tests for BD, and found that Mendelian disease genes are enriched in the top results from both tests (OR=20.3, p=1×10 −3 ; OR=2.2, p=1×10 −2 ). We next identified a set of Mendelian variants that co-occur in individuals with BD more frequently than their unaffected family members, including the R3527Q mutation in APOB associated with hypercholesterolemia. Using polygenic risk scores, we demonstrated that BD individuals from this pedigree were enriched for the same common risk-alleles for BD as in the general population (β=0.416, p=6×10 −4 ). Furthermore, in the extended Amish family we find evidence for a common genetic etiology between BD and clinical autoimmune thyroid disease (p=1×10 −4 ), diabetes (p=1×10 −3 ), and lipid traits such as triglyceride levels (p=3×10 −4 ). We identify genomic regions that contribute to the differences between BD individuals and unaffected family members by calculating local genetic risk for independent LD blocks. Our findings provide evidence for the extensive genetic pleiotropy that can drive epidemiological findings of comorbidities between diseases and other complex traits. Identifying such patterns may enable the subtyping of complex diseases and facilitate our understanding of the genetic mechanisms underlying phenotypic heterogeneity.

Genetic pleiotropy between mood disorders, metabolic, and endocrine traits in a multigenerational pedigree