DNA sequence-level analyses reveal potential phenotypic modifiers in a large family with psychiatric disorders

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.

Familial t(1;11) translocation is associated with disruption of white matter structural integrity and oligodendrocyte–myelin dysfunction

“…All eight carriers had a psychiatric diagnosis; one with SZ, four with major depression (MDD), three with cyclothymia while only 1 of the 13 family members without the t (1;11) translocation, had a psychiatric diagnosis [27]. The affected noncarrier however is described to carry modifier loci on chr11q2 and chr5q that might contribute to the development of MMI (described in [28]). High-resolution T1-weighted structural and dMRI data were combined to create structural connectivity matrices of each participant's brain.…”

Disrupted‐in‐schizophrenia 1 functional polymorphisms and D2/D3 receptor availability: A [11C]‐(+)‐PHNO imaging study

“…We have recently shown association between the serine allele of Ser704Cys and increased striatal dopamine synthesis capacity in healthy participants . Interestingly, recent studies indicate the t (1;11) translocation may increase the risk of psychosis through various other mechanisms, including altered DNA methylation, regulation of N‐methyl‐D‐aspartate receptors (NMDAR) motility and/oradded effects of the translocation and a variable subset of potential phenotypic polymorphisms . Future studies should aim at clarifying how the DISC1 protein interacts with the D 2 R and whether the DISC1 Ser704Cys, Leu607Phe and Arg264Gln polymorphisms affect D 2 R availability in clinical populations.…”

Familial t(1;11) translocation is associated with disruption of white matter structural integrity and oligodendrocyte-myelin dysfunction

“…All 8 carriers had a psychiatric diagnosis; 1 with schizophrenia, 4 with major depression (MDD), 3 with cyclothymia while only 1 of the 13 family members who did not have the t(1;11) translocation, had a psychiatric diagnosis 27 . The affected non-carrier however is described to carry modifier loci on chr11q2 and chr5q that might contribute to the development of MMI (described in 28 ). High resolution T1-weighted structural and dMRI data were combined to create structural connectivity matrices of each participant's brain.…”