Rare susceptibility variants for bipolar disorder suggest a role for G protein-coupled receptors

Cruceanu, Cristiana; Jf, Schmouth; Torres-Platas, Susana G.; Jp, Lopez; Ambalavanan, Amirthagowri; Darcq, Emmanuel; Gross, Florence; Breton, Billy; Spiegelman, Dan; Rochefort, Daniel; Hince, Pascale; Jm, Petite; Gauthier, Josée; Rg, Lafrenière; Pa, Dion; Greenwood, Celia M.T.; Bl, Kieffer; Alda, Martin; Turecki, Gustavo; Ga, Rouleau

doi:10.1038/mp.2017.223

Cited by 32 publications

(28 citation statements)

References 38 publications

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“…Further, we have only assessed the shared common genetic variants between AD and BIP. Other genetic variations, like rare structural variants, are also shown to increase the risk of AD and BIP (Lord et al, 2014; Cruceanu et al, 2017). Lastly, most participants in the data used in our study are of European ancestry.…”

Section: Discussionmentioning

confidence: 99%

Genetic Overlap Between Alzheimer’s Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes

Drange¹,

Smeland²,

Shadrin³

et al. 2019

Front. Neurosci.

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Background: Alzheimer’s disease (AD) and bipolar disorder (BIP) are complex traits influenced by numerous common genetic variants, most of which remain to be detected. Clinical and epidemiological evidence suggest that AD and BIP are related. However, it is not established if this relation is of genetic origin. Here, we applied statistical methods based on the conditional false discovery rate (FDR) framework to detect genetic overlap between AD and BIP and utilized this overlap to increase the power to identify common genetic variants associated with either or both traits.Methods: We obtained genome wide association studies data from the International Genomics of Alzheimer’s Project part 1 (17,008 AD cases and 37,154 controls) and the Psychiatric Genetic Consortium Bipolar Disorder Working Group (20,352 BIP cases and 31,358 controls). We used conditional QQ-plots to assess overlap in common genetic variants between AD and BIP. We exploited the genetic overlap to re-rank test-statistics for AD and BIP and improve detection of genetic variants using the conditional FDR framework.Results: Conditional QQ-plots demonstrated a polygenic overlap between AD and BIP. Using conditional FDR, we identified one novel genomic locus associated with AD, and nine novel loci associated with BIP. Further, we identified two novel loci jointly associated with AD and BIP implicating the MARK2 gene (lead SNP rs10792421, conjunctional FDR = 0.030, same direction of effect) and the VAC14 gene (lead SNP rs11649476, conjunctional FDR = 0.022, opposite direction of effect).Conclusion: We found polygenic overlap between AD and BIP and identified novel loci for each trait and two jointly associated loci. Further studies should examine if the shared loci implicating the MARK2 and VAC14 genes could explain parts of the shared and distinct features of AD and BIP.

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Section: Discussionmentioning

confidence: 99%

Genetic Overlap Between Alzheimer’s Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes

Drange¹,

Smeland²,

Shadrin³

et al. 2019

Front. Neurosci.

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“…However, given the modest effect sizes of the PRS, they explained only a fraction of the phenotypic variance, and rare mutations such as copy number variants [50] or rare single-nucleotide variants likely also play an important role in each of the families. Sequencing studies carried out in multiplex families have suggested rare variants are involved in the aetiology of BD [51][52][53]. To date, however, it has proven difficult to identify replicable causal associations between rare variants and BD susceptibility.…”

Section: ×10 -4mentioning

confidence: 99%

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

et al. 2019

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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.

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“…The LRBest group showed a later age of onset (median 28y, interquartile range, IQR [21, 36]) compared to NRBest (median 19, IQR [16, 24]; p<0.00001).…”

Section: Resultsmentioning

confidence: 99%

Exemplar Scoring Identifies Genetically Separable Phenotypes of Lithium Responsive Bipolar Disorder

Nunes

Stone

Ardau³

et al. 2020

Preprint

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Predicting lithium response (LiR) in bipolar disorder (BD) could expedite effective pharmacotherapy, but phenotypic heterogeneity of bipolar disorder has complicated the search for genomic markers. We thus sought to determine whether patients with "exemplary phenotypes"---those whose clinical features are reliably predictive of LiR and non-response (LiNR)---are more genetically separable than those with less exemplary phenotypes. We applied machine learning methods to clinical data collected from people with BD (n=1266 across 7 international centres; 34.7% responders) to compute an "exemplar score", which identified a subset of subjects whose clinical phenotypes were most robustly predictive of LiR/LiNR. For subjects whose genotypes were available (n=321), we evaluated whether responders/non-responders with exemplary phenotypes could be more accurately classified based on genetic data than those with non-exemplary phenotypes. We showed that the best LiR exemplars had later illness onset, completely episodic clinical course, absence of rapid cycling and psychosis, and few psychiatric comorbidities. The best exemplars of LiR and LiNR were genetically separable with an area under the receiver operating characteristic curve of 0.88 (IQR [0.83, 0.98]), compared to 0.66 [0.61, 0.80] (p=0.0032) among the poor exemplars. Variants in the Alzheimer's amyloid secretase pathway, along with G-protein coupled receptor, muscarinic acetylcholine, and histamine H1R signaling pathways were particularly informative predictors. In sum, the most reliably predictive clinical features of LiR and LiNR patients correspond to previously well-characterized phenotypic spectra whose genomic profiles are relatively distinct. Future work must enlarge the sample for genomic classification and include prediction of response to other mood stabilizers.

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Rare susceptibility variants for bipolar disorder suggest a role for G protein-coupled receptors

Cited by 32 publications

References 38 publications

Genetic Overlap Between Alzheimer’s Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes

Genetic Overlap Between Alzheimer’s Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes

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

Exemplar Scoring Identifies Genetically Separable Phenotypes of Lithium Responsive Bipolar Disorder

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