Abstract
Psychiatric disorders are a group of genetically related diseases with highly polygenic architectures. Genome-wide association analyses have made substantial progress towards understanding the genetic architecture of these disorders. More recently, exome- and whole-genome sequencing of cases and families have identified rare, high penetrant variants that provide direct functional insight. There remains, however, a gap in the heritability explained by these complementary approaches. To understand how multiple genetic variants combine to modify both severity and penetrance of a highly penetrant variant, we sequenced 48 whole genomes from a family with a high loading of psychiatric disorder linked to a balanced chromosomal translocation. The (1;11)(q42;q14.3) translocation directly disrupts three genes: DISC1, DISC2, DISC1FP and has been linked to multiple brain imaging and neurocognitive outcomes in the family. Using DNA sequence-level linkage analysis, functional annotation and population-based association, we identified common and rare variants in GRM5 (minor allele frequency (MAF) > 0.05), PDE4D (MAF > 0.2) and CNTN5 (MAF < 0.01) that may help explain the individual differences in phenotypic expression in the family. We suggest that whole-genome sequencing in large families will improve the understanding of the combined effects of the rare and common sequence variation underlying psychiatric phenotypes.
Highlights
Members of the family carry a balanced translocation between chromosomes 1 and 11 (1q42; 11q14.3, hereafter t (1;11)) that is significantly linked to major mental illness, with a maximum logarithm of the odds (LOD) score of 7.9 for a broad model including individuals with SCZ, bipolar disorder (BD), schizoaffective disorder (SCZAFF), recurrent major depressive disorder (MDD), cyclothymia, single episode MDD plus minor diagnoses [18]
The final dataset included 9.76 million single-nucleotide variants (SNVs) present in at least one individual of which 16.46 and 5.80% were not found in the 1000 Genomes phase 3 European [28] or gnomAD non-Finnish European subsets, respectively, and 5.41% were found in neither repository (July 1017; Supplementary figure 1b: Minor allele frequencies (MAF) of SNVs in 1000 Genomes phase 3 European sample (EUR) and GnomAD non-Finnish European (NFE))
The maximum theoretical LOD and the observed two-point LOD for the translocation was generated for each model using only the set of family members sequenced in this study
Summary
These authors jointly supervised this work: David J. Members of the family carry a balanced translocation between chromosomes 1 and 11 (1q42; 11q14.3, hereafter t (1;11)) that is significantly linked to major mental illness, with a maximum logarithm of the odds (LOD) score of 7.9 for a broad model including individuals with SCZ, BD, schizoaffective disorder (SCZAFF), recurrent MDD (rMDD), cyclothymia, single episode MDD (sMDD) plus minor diagnoses (including: alcoholism, adolescent conduct disorder and anxiety) [18]. We combined genome-wide variance component multipoint linkage, regional two-point linkage and haplotype analyses on the full spectrum of variants within the t(1;11) family to identify additional potential risk/ modifier loci and tested the association of these loci in two case–control samples drawn from the UK population
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