Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders

Abstract

Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development.

Clinical and genetic differences between bipolar disorder type 1 and 2 in multiplex families

“…Genomewide genotyping was carried out using the Illumina Infinium PsychArray BeadChip (PsychChip). All quality control (QC) and imputation procedures have been described previously 28 . In brief, QC and population substructure analyses were performed in PLINK v1.9 33 , as described in the Supplementary Methods.…”

“…We analyzed the association of PRS with all dichotomous phenotypes showing a p < 5.56 × 10 −03 in GEE analyses (see above). PRS analyses were carried out as previously described 28 in R using the function glmm. wald of the package GMMAT 42 , fitted by maximum likelihood using Nelder-Mead optimization.…”

“…In a previous study on BD multiplex families, Frankland et al 26 described more mixed states in BD-II and more psychomotor retardation as well as more psychotic features of depressive episodes in BD-I cases. We have previously shown that, compared to unaffected family members and unrelated controls, BD patients from multiplex families have a high genetic risk load specifically for BD 27,28 . Furthermore, family members also had a higher genetic risk load for SCZ and, to a lesser degree, for MDD than unrelated controls 28 .…”

“…We have previously shown that, compared to unaffected family members and unrelated controls, BD patients from multiplex families have a high genetic risk load specifically for BD 27,28 . Furthermore, family members also had a higher genetic risk load for SCZ and, to a lesser degree, for MDD than unrelated controls 28 . Therefore, we hypothesize that a correlation between the genetic risk burden for psychiatric disorders and disease severity exists in these families.…”

LDB2 locus disruption on 4p16.1 as a risk factor for schizophrenia and bipolar disorder

“…A number of rare variants have been identified till date, with far larger effects on individual risk; de-novo mutations have also been reported to confer substantial individual risk 2,3 . Increasing evidence has suggested an overlap of genetic susceptibility between schizophrenia and bipolar disorder 4,5 . Most notable association has been found with the Disrupted In Schizophrenia 1 (DISC1) gene, based upon chromosomal abnormality with a balanced chromosomal translocation (1;11)(q42;q14.3) in a large pedigree 6,7 .…”