Whole genome linkage analysis in a large Brazilian multigenerational family reveals distinct linkage signals for Bipolar Disorder and Depression.

Both common and rare genetic variation play a role in the causes for mood disorders. Very large families pose unique opportunities and analytical challenges but may provide a way to identify regions and mutations associated with mood disorders. We identified a family with a high prevalence (~30%) of mood disorders in a rural village in Brazil, featuring decreasing age of onset over generations. The pattern of inheritance was complex with 32 Bipolar type I cases, 11 Bipolar type II and 59 recurrent and/or severe Depression cases in addition to other phenotypes. We enrolled 333 participants with DNA samples from a broader pedigree of 960 subjects for genotyping using the Affymetrix 10K array. Non-parametric linkage was carried out via MERLIN and parametric with both MERLIN and MCLINKAGE. We exome sequenced a subset of the family (n=27) in order to identify rare variation within the linkage regions shared by affected family members. We identified four genome wide significant and four suggestive linkage regions on chromosomes 1, 2, 3, 11 and 12 for different phenotype definitions. However, no region received strong joint support in both the parametric and non-parametric analyses. Exome sequencing revealed potential deleterious variants in 11p15.4 for MDD and 1q21.1-1q21.3 and 12p23.1-p22.3, implicated in cell signaling, adhesion, translation and neurogenesis processes. Overall, our results suggest promising, but not definitive or confirmed evidence, that rare genetic variation contributes to the high prevalence of mood disorders in this multi-generational family. We note that a substantial role for common genetic variation is likely given the strength of the linkage signals observed.