Assessment of first and second degree relatives of individuals with bipolar disorder shows increased genetic risk scores in both affected relatives and young At‐Risk Individuals

Abstract

Recent studies have revealed the polygenic nature of bipolar disorder (BP), and identified common risk variants associated with illness. However, the role of common polygenic risk in multiplex families has not previously been examined. The present study examined 249 European‐ancestry families from the NIMH Genetics Initiative sample, comparing subjects with narrowly defined BP (excluding bipolar II and recurrent unipolar depression; n = 601) and their adult relatives without BP (n = 695). Unrelated adult controls (n = 266) were from the NIMH TGEN control dataset. We also examined a prospective cohort of young (12–30 years) offspring and siblings of individuals with BPI and BPII disorder (at risk; n = 367) and psychiatrically screened controls (n = 229), ascertained from five sites in the US and Australia and assessed with standardized clinical protocols. Thirty‐two disease‐associated SNPs from the PGC‐BP Working Group report (2011) were genotyped and additive polygenic risk scores (PRS) derived. We show increased PRS in adult cases compared to unrelated controls (P = 3.4 × 10−5, AUC = 0.60). In families with a high‐polygenic load (PRS score ≥32 in two or more subjects), PRS distinguished cases with BPI/SAB from other relatives (P = 0.014, RR = 1.32). Secondly, a higher PRS was observed in at‐risk youth, regardless of affected status, compared to unrelated controls (GEE‐χ2 = 5.15, P = 0.012). This report is the first to explore common polygenic risk in multiplex families, albeit using only a small number of robustly associated risk variants. We show that individuals with BP have a higher load of common disease‐associated variants than unrelated controls and first‐degree relatives, and illustrate the potential utility of PRS assessment in a family context. © 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

Neurocognitive functioning in euthymic patients with bipolar disorder and unaffected relatives: A review of the literature

“…Future studies might benefit from direct measures of genetic and environmental risk factors shared by patients and individuals at familial risk. Polygenic risk scores provide one way to assess genetic risk, but account for only a small portion of the variance in risk for illness and are often strongly cor-related among close relatives (Fullerton et al, 2015). Non-genetic risk factors, such as head injury, are rarely assessed but could play an important contributory role (Chi et al, 2015; Deb et al, 1999; Jorge and Robinson, 2003).…”

Traumatic Stress Interacts With Bipolar Disorder Genetic Risk to Increase Risk for Suicide Attempts

“…DNA was extracted from whole blood by the Rutgers University Cell and DNA Repository (New Brunswick, NJ; US participants) or Genetic Repositories Australia (Sydney, NSW, Australia; Australian participants), as previously described. 39 Genome-wide SNP genotyping was conducted using the Infinium PsychArray BeadChip (Illumina, Scoresby, VIC, Australia) at the Mt. Sinai School of Medicine Genomics Core Facility, with genotype calling and quality control conducted using standard Psychiatric Genomics Consortium (PGC) pipelines.…”

Towards person-centered neuroimaging markers for resilience and vulnerability in Bipolar Disorder

“…A further challenge lies in predicting the outcome of asymptomatic individuals with a family history of BD. As a group, these individuals are a higher risk than the general population for developing BD (Duffy et al, 2015; Fullerton et al, 2015). …”