M65 - EXOME SEQUENCING OF MULTIPLEX PEDIGREES WITH EARLY ONSET, RECURRENT MAJOR DEPRESSIVE DISORDER

Abstract

Background Major Depressive Disorder (MDD) is a common, often impairing disorder that ranks as the second leading cause of disability worldwide. More effective treatments are urgently needed, but few novel treatments have been developed over the last several decades, in large part due to our limited understanding of the pathophysiology of MDD. A long history of family and twin studies has shown consistent evidence for significant heritability in MDD and recent large scale GWAS analyses have begun to identify strongly associated common variants. However, few studies have so far focused on rare more penetrant variants, which may provide more interpretable insights into MDD related biology. Methods We selected 25 multiplex families from the Genetics of Early Onset Depression cohort, hypothesizing that pedigrees with at least three family members with childhood-onset depression, would be enriched for highly penetrant rare variants. We have completed exome sequencing in 3 affected members from these 25 highly multiplex families to average depth of 50X. Alignment and genotyping was performed employing standard pipelines using BWA-mem and GATK. Given prior evidence that ultra-rare variation may be most likely associated with greater penetrance, we focused our analyses on singly-segregating variants, defined as variants that fully segregated in a single family and were absent in all other pedigrees. Annotation was performed with ANNOVAR. Selected variants were confirmed with sanger sequencing. Results Each of the 25 multiplex families had an average of 4,092 segregating variants of which 412 were rare (defined as minor allele frequency Discussion Our study represents one of the first family based exome sequencing studies of major depression using an early onset, multiplex sample. We have found a number of highly damaging segregating variants that may be associated with MDD. Additional ongoing analyses, including pathway enrichment and replication, will also be presented.