Common and Rare Variant Analysis in Early-Onset Bipolar Disorder Vulnerability

Jamain, Stéphane; Cichon, Sven; Étain, Bruno; Mühleisen, Thomas W.; Georgi, Alexander; Zidane, Nora; Chevallier, Lucie; Deshommes, Jasmine; Nicolas, Aude; Henrion, A.; Degenhardt, Franziska; Mattheisen, Manuel; Priebe, Lutz; Mathieu, Flavie; Kahn, Jean‐Pierre; Henry, Chantal; Boland, Anne; Zélénika, Diana; Gut, Marta; Heath, Simon; Lathrop, Mark; Maier, Wolfgang; Albus, Margot; Rietschel, Marcella; Schulze, Thomas G.; McMahon, Francis J.; Kelsoe, John R.; Hamshere, Marian L.; Craddock, Nicholas John; Nöthen, Markus M.; Bellivier, Frank; Leboyer, Marion

doi:10.1371/journal.pone.0104326

Cited by 37 publications

(29 citation statements)

References 48 publications

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“…Participants from Paris were genotyped using Illumina SNP assays, with CNG standardized quality control described in detail in Jamain et al (2014). 26 For the French population, the quality control was performed using the PLINK toolset on a total of 317 131 commons SNPs genotyped in 2043 DNA samples. We removed monomorphic SNPs, as those with a minor allele frequency (MAF) lower than 0.01 and SNPs with a call rate lower than 0.97.…”

Section: Polygenic Risk Scores (Prs)mentioning

confidence: 99%

Childhood maltreatment and polygenic risk in bipolar disorders

et al. 2019

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Background Childhood maltreatment is a well‐known risk factor for developing a more severe and complex form of bipolar disorders (BD). However, knowledge is scarce about the interactions between childhood maltreatment and underlying genetic vulnerability on the clinical expression of BD. Method We assigned a BD‐polygenic risk score (BD‐PRS), calculated from the Psychiatric Genomics Consortium, to each individual in a sample of 402 cases with BD. The lifetime clinical expression of BD was characterized using structured interviews and patients completed the Childhood Trauma Questionnaire (CTQ) to assess the severity of childhood maltreatment. Results Cases who reported more severe childhood maltreatment had a lower BD‐PRS (rho = −0.12, P = .01), especially when considering emotional abuse (rho = −0.16, P = .001). An interaction between BD‐PRS and childhood maltreatment was observed for the risk of rapid cycling (P = .01). No further interactions between BD‐PRS and childhood maltreatment were observed for other clinical characteristics (age at onset, suicide attempts, number of mood episodes, mixed features, substance use disorders and psychotic symptoms). Conclusion Our study is the first to show that less genetic risk may be needed to develop a more unstable form of BD when exposed to childhood maltreatment. Our study supports childhood trauma as an independent risk factor for BD.

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Section: Polygenic Risk Scores (Prs)mentioning

confidence: 99%

Childhood maltreatment and polygenic risk in bipolar disorders

et al. 2019

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“…After this review, a subset of adult patients (n=192) was classified as having early-onset BD. Patients were classified as having early-onset BD if their first manic or depressive episode occurred at age 19 years or younger (3,25,26). This early-onset characterization was independently confirmed for each patient by 2 child and adolescent psychiatrists (P.E.C.…”

Section: Methodsmentioning

confidence: 99%

Genetic Risk Score Analysis in Early-Onset Bipolar Disorder

Croarkin

Luby

Cercy

et al. 2017

J. Clin. Psychiatry

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Objective In this study, we performed a candidate genetic risk score (GRS) analysis of early-onset bipolar disorder. Method Treatment of Early Age Mania (TEAM) study enrollment and sample collection took place from 2003–2008. Mayo Clinic Bipolar Biobank samples were collected from 2009–2013. Genotyping and analyses for the present study took place from 2013–2014. The diagnosis of bipolar disorder was based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. Eight single-nucleotide polymorphisms (SNPs), previously reported in genome-wide association studies to be associated with bipolar disorder, were chosen for GRS analysis in early-onset bipolar disease. These SNPs map to 3 genes: CACNA1C (calcium channel, voltage-dependent, L type, alpha 1C subunit), ANK3 (ankyrin-3, node of Ranvier [ankyrin G]), and ODZ4 (teneurin transmembrane protein 4 [formerly “odz, odd Oz/ten-m homolog 4 {Drosophila}, ODZ4”]). The 8 candidate SNPs were genotyped in patients from the TEAM study (n=69), adult patients with bipolar disorder (n=732) including a subset with early-onset illness [n=192]), and healthy controls (n=776). GRS analyses were performed comparing early-onset cases with controls. In addition, associations of early-onset BD with individual SNPs and haplotypes were explored. Results GRS analysis revealed associations of the risk score with early-onset bipolar disorder (P=.01). Gene-level haplotype analysis comparing TEAM patients with controls suggested association of early-onset bipolar disorder with a CACNA1C haplotype (global test, P=.01). At the level of individual SNPs, comparison of TEAM cases with healthy controls provided nominally significant evidence for association of SNP rs10848632 in CACNA1C with early-onset bipolar disorder (P=.017), which did not remain significant after correction for multiple comparisons. Conclusion These preliminary analyses suggest that previously identified bipolar disorder risk loci, especially CACNA1C, have a role in early-onset bipolar disorder, possibly with stronger effects than for late-onset bipolar disorder.

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“…All patients met the DSM-IV diagnostic criteria for BD. In addition, a previously published cohort 19,20 of 445 subjects with BD and 1636 control individuals of French origin has been used for genotyping analyses ( Supplementary Fig. S2).…”

Section: Cohortsmentioning

confidence: 99%

Contribution of common and rare damaging variants in familial forms of bipolar disorder and phenotypic outcome

et al. 2020

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Genome-wide association studies on bipolar disorders (BD) have revealed an additive polygenic contribution of common single-nucleotide polymorphisms (SNPs). However, these SNPs explain only 25% of the overall genetic variance and suggest a role of rare variants in BD vulnerability. Here, we combined high-throughput genotyping data and whole-exome sequencing in cohorts of individuals with BD as well as in multiplex families with a high density of affected individuals in order to determine the contribution of both common and rare variants to BD genetic vulnerability. Using polygenic risk scores (PRS), we showed a strong contribution of common polymorphisms previously associated with BD and schizophrenia (SZ) and noticed that those specifically associated with SZ contributed more in familial forms of BD than in non-familial ones. The analysis of rare damaging variants shared by affected individuals in multiplex families with BD revealed a single interaction network enriched in neuronal and developmental biological pathways, as well as in the regulation of gene expression. We identified four genes with a higher mutation rate in individuals with BD than in the general population and showed that mutations in two of them were associated with specific clinical manifestations. In addition, we showed a significant negative correlation between PRS and the number of rare damaging variants specifically in unaffected individuals of multiplex families. Altogether, our results suggest that common and rare genetic variants both contribute to the familial aggregation of BD and this genetic architecture may explain the heterogeneity of clinical manifestations in multiplex families.

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Common and Rare Variant Analysis in Early-Onset Bipolar Disorder Vulnerability

Cited by 37 publications

References 48 publications

Childhood maltreatment and polygenic risk in bipolar disorders

Childhood maltreatment and polygenic risk in bipolar disorders

Genetic Risk Score Analysis in Early-Onset Bipolar Disorder

Contribution of common and rare damaging variants in familial forms of bipolar disorder and phenotypic outcome

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