The Heritability of Bipolar Affective Disorder and the Genetic Relationship to Unipolar Depression

McGuffin, Peter; Rijsdijk, Frühling; Andrew, Martin; Sham, Pak C.; Katz, Randy; Cardno, Alastair G.

doi:10.1001/archpsyc.60.5.497

Cited by 1,116 publications

(721 citation statements)

References 21 publications

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“…Intriguingly, a recent twin study suggests that the genetic vulnerability for mania and depression, although related, is separable (McGuffin et al, 2003). It is important to distinguish depression from mania in studies of psychosocial predictors (Johnson and Kizer, 2002) and neurotransmitter correlates (Joffe, Young, & MacQueen, 1999).…”

Section: Polarity-specific Effectsmentioning

confidence: 99%

Life events in bipolar disorder: Towards more specific models

Johnson

2005

Clinical Psychology Review

182

167

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This article reviews the evidence concerning life events as a predictor of symptoms within bipolar disorder. First, key methodological issues in this area are described, and criteria used for including studies in this review are defined. Then findings that negative life events predict worse outcomes within bipolar disorder are reviewed. Beyond general studies on relapse, it is important to differentiate predictors of depression from predictors of mania. When severe negative life events occur, they appear to trigger increases in bipolar depression. Nonetheless, many depressions are unrelated to negative life events and appear to be triggered by other variables. The strongest evidence suggests that negative life events do not trigger mania, except perhaps in certain contexts. Retrospective findings for schedule-disrupting life events as a trigger for manic symptoms await further assessment within a longitudinal study. Life events involving goal attainment do appear to trigger manic symptoms. Overall, it is time to differentiate among specific types of life events, as these different forms of events point towards mechanisms linking stressors with symptom expression. These mechanisms provide clues into ways to integrate the social environment with biological vulnerability (see Bipolar disorder is clearly a biological disorder. Nonetheless, over the past 15 years, a wealth of research has made it abundantly clear that psychosocial variables shape outcomes of this disorder. Much of this psychosocial research has focused on whether life events predict the timing and severity of symptoms within this disorder. This paper reviews the evidence that life events are related to symptom expression within bipolar disorder. This basic question has challenged researchers for over 20 years. Given the growing literature, this paper focus on addressing two more specific questions. Which types of symptoms are related to life events? What types of life events influence symptoms? Given the growing number of studies available on these issues, this review will focus on those studies with the most rigorous methodologies. To set the stage for this endeavor, it is important to first review the major methodological issues in research on life events and bipolar disorder, including issues related to design, measurement, and sampling.

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Section: Polarity-specific Effectsmentioning

confidence: 99%

Life events in bipolar disorder: Towards more specific models

Johnson

2005

Clinical Psychology Review

182

167

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“…However, despite phenotypic aggregation within families [McGuffin et al, 2003; Lichtenstein et al, 2009], no studies have so far examined polygenic risk incorporating these common genetic factors in a family context in adults, with only one group to date reporting on polygenic risk in adolescent offspring of individuals with BP [Whalley et al, 2012, 2013]. …”

Section: Introductionmentioning

confidence: 99%

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

Fullerton

Koller

Edenberg

et al. 2015

American J of Med Genetics Pt B

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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.

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“…1 Twin, family and adoption studies have suggested that genetic factors are involved in BD, but no causal mutation has yet been identified. 2 The identification of susceptibility genes has been hampered by a lack of consensus concerning the most valid phenotype to investigate and by the unknown genetic validity of the classical clinical classifications. To disentangle the genetic and clinical heterogeneity of the disorder, a clinical approach based on candidate symptoms has been proposed.…”

Section: Introductionmentioning

confidence: 99%

A SNAP25 promoter variant is associated with early-onset bipolar disorder and a high expression level in brain

et al. 2009

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Bipolar disorder (BD) is one of the most common and persistent psychiatric disorders. Earlyonset BD has been shown to be the most severe and familial form. We recently carried out a whole-genome linkage analysis on sibpairs affected by early-onset BD and showed that the 20p12 region was more frequently shared in our families than expected by chance. The synaptosomal-associated protein SNAP25 is a presynaptic plasma membrane protein essential for the triggering of vesicular fusion and neurotransmitter release, and for which abnormal protein levels have been reported in postmortem studies of bipolar patients. We hypothesised that variations in the gene encoding SNAP25, located on chromosome 20p12, might influence the susceptibility to early-onset BD. We screened SNAP25 for mutations and performed a case-control association study in 197 patients with early-onset BD, 202 patients with late-onset BD and 136 unaffected subjects. In addition, we analysed the expression level of the two SNAP25 isoforms in 60 brains. We showed that one variant, located in the promoter region, was associated with early-onset BD but not with the late-onset subgroup. In addition, individuals homozygous for this variant showed a significant higher SNAP25b expression level in prefrontal cortex. These results show that variations in SNAP25, associated with an increased gene expression level in prefrontal cortex, might predispose to early-onset BD. Further analyses of this gene, as well as analysis of genes encoding for the SNAP25 protein partners, are required to understand the impact of such molecular mechanisms in BD.

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The Heritability of Bipolar Affective Disorder and the Genetic Relationship to Unipolar Depression

Abstract: As defined by the DSM-IV, BPD is highly heritable. There are substantial genetic and nonshared environmental correlations between mania and depression, but most of the genetic variance in liability to mania is specific to the manic syndrome.

Cited by 1,116 publications

References 21 publications

Life events in bipolar disorder: Towards more specific models

Life events in bipolar disorder: Towards more specific models

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

A SNAP25 promoter variant is associated with early-onset bipolar disorder and a high expression level in brain

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