BEYOND THE TRANSLOCATION: WHOLE GENOME SEQUENCING ANALYSIS OF THE SCOTTISH T(1;11) FAMILY

Background Psychiatric illnesses are a group of genetically-related disorders with highly polygenic architecture and a significant environmental component. Even within families, these conditions show the attributes of many complex traits: reduced penetrance and phenotypic heterogeneity. An extended pedigree design has several advantages: it avoids population stratification and reduces genetic heterogeneity, narrowing the search for rare and functional variants that segregate with a phenotype. We have analysed a multigenerational pedigree where major mental illness segregates with a balanced translocation between chromosomes 1 and 11. Methods Whole genome sequencing was performed on 49 family members (20 carriers, 29 non-carriers of the translocation). Polygenic risk scores were calculated using summary statistics from the PGC MDD 2011 and used to predict diagnosis. Multipoint linkage analyses were performed using the variance components method implemented in SOLAR. Multiple phenotypic classes were used constructed to reflect the multiple phenotypes within the family. Fine-mapping was performed using two-point linkage analyses across the linked regions and association analyses performed in a Scottish cohort with measures of mental health, cognitive and personality traits (N= 6,555; 2,060 cases and 4,495 controls). Results Two genome-wide significant peaks with LOD > 5.5 were detected on the translocated chromosomes 1 and 11 with maximum linkage to schizophrenia, bipolar disorder, recurrent major depression and cyclothymia; as previously noted for the translocation itself. In addition, two further peaks, a second on chromosome 1 and a peak on chromosome 5, showed genome-wide significant linkage to affective disorder (bipolar disorder, and major depressive disorder). Polygenic risk scores of schizophrenia and bipolar disorder, but not major depressive disorder significantly predict mental illness in the family. Functional annotation of the whole genome sequence, and case-control association for affective disorder in the Scottish population, support a role for GRM5, CNTN5 and PDE4D in the phenotypic heterogeneity seen in the family. Discussion These results suggest that the high density of psychiatric illness in the t(1;11) family may be a combination of: direct effects of the translocation on the genes located at the breakpoint (DISC1, DISC2, DISC1FP), “locking together” of additional familial risk factors and the accumulation of common risk variants. We have identified additional modifying loci that may explain the variance in disease expression. Our findings suggest that pleiotropy may play a significant role and that this is now tractable by whole genome sequencing in families.