Identification of potential genetic risk factors for bipolar disorder by whole-exome sequencing

Husson, Thomas; Duboc, Jean-Baptiste; Quenez, Olivier; Charbonnier, Camille; Rothärmel, Maud; Cuenca, Macarena; Jegouzo, Xavier; Richard, Anne-Claire; Frébourg, Thierry; Deleuze, Jean‐François; Boland, Anne; Génin, Emmanuelle; Debette, Stéphanie; Tzourio, Christophe; Campion, Dominique; Nicolas, Gaël; Guillin, Olivier

doi:10.1038/s41398-018-0291-7

Cited by 17 publications

(9 citation statements)

References 42 publications

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“…For example, an extreme phenotype strategy aims at identifying rare variants with large effect sizes through recruitment of patients with traits at either end of the phenotypic spectrum. These phenotypes can be based on family history, age of onset, outcome, severity scores, biomarker levels, disease trajectory or response to treatment [30][31][32]. Such stratification was proven to increase the power to detect novel disease risk genes [30,33,34] and to be cost-effective [35].…”

Section: Forward Phenotyping For Genetic Studiesmentioning

confidence: 99%

‘There and Back Again’—Forward Genetics and Reverse Phenotyping in Pulmonary Arterial Hypertension

Swietlik

Prapa

Martin

et al. 2020

Genes

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Although the invention of right heart catheterisation in the 1950s enabled accurate clinical diagnosis of pulmonary arterial hypertension (PAH), it was not until 2000 when the landmark discovery of the causative role of bone morphogenetic protein receptor type II (BMPR2) mutations shed new light on the pathogenesis of PAH. Since then several genes have been discovered, which now account for around 25% of cases with the clinical diagnosis of idiopathic PAH. Despite the ongoing efforts, in the majority of patients the cause of the disease remains elusive, a phenomenon often referred to as “missing heritability”. In this review, we discuss research approaches to uncover the genetic architecture of PAH starting with forward phenotyping, which in a research setting should focus on stable intermediate phenotypes, forward and reverse genetics, and finally reverse phenotyping. We then discuss potential sources of “missing heritability” and how functional genomics and multi-omics methods are employed to tackle this problem.

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Section: Forward Phenotyping For Genetic Studiesmentioning

confidence: 99%

‘There and Back Again’—Forward Genetics and Reverse Phenotyping in Pulmonary Arterial Hypertension

Swietlik

Prapa

Martin

et al. 2020

Genes

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“…We first check our variants’ loci in an internal control series, consisting of exome samples (N = 288) of Eastern European ancestries, collected as non-cancer controls as part of our previous lung cancer susceptibility study [ 50 ], and processed similarly to internal cases. Candidate variants were then searched within a French reference panel available through the French Exome Project (FrEx) database (N = 574) to check for potential population-specific recurrent variation that would be unlikely to cause the observed phenotype ( , accessed on 25 January 2021) [ 51 ].…”

Section: Methodsmentioning

confidence: 99%

The PI3K/mTOR Pathway Is Targeted by Rare Germline Variants in Patients with Both Melanoma and Renal Cell Carcinoma

Hubert

Suybeng

Vallée

et al. 2021

Cancers

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Background: Malignant melanoma and RCC have different embryonic origins, no common lifestyle risk factors but intriguingly share biological properties such as immune regulation and radioresistance. An excess risk of malignant melanoma is observed in RCC patients and vice versa. This bidirectional association is poorly understood, and hypothetic genetic co-susceptibility remains largely unexplored. Results: We hereby provide a clinical and genetic description of a series of 125 cases affected by both malignant melanoma and RCC. Clinical germline mutation testing identified a pathogenic variant in a melanoma and/or RCC predisposing gene in 17/125 cases (13.6%). This included mutually exclusive variants in MITF (p.E318K locus, N = 9 cases), BAP1 (N = 3), CDKN2A (N = 2), FLCN (N = 2), and PTEN (N = 1). A subset of 46 early-onset cases, without underlying germline variation, was whole-exome sequenced. In this series, thirteen genes were significantly enriched in mostly exclusive rare variants predicted to be deleterious, compared to 19,751 controls of similar ancestry. The observed variation mainly consisted of novel or low-frequency variants (<0.01%) within genes displaying strong evolutionary mutational constraints along the PI3K/mTOR pathway, including PIK3CD, NFRKB, EP300, MTOR, and related epigenetic modifier SETD2. The screening of independently processed germline exomes from The Cancer Genome Atlas confirmed an association with melanoma and RCC but not with cancers of established differing etiology such as lung cancers. Conclusions: Our study highlights that an exome-wide case-control enrichment approach may better characterize the rare variant-based missing heritability of multiple primary cancers. In our series, the co-occurrence of malignant melanoma and RCC was associated with germline variation in the PI3K/mTOR signaling cascade, with potential relevance for early diagnostic and clinical management.

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“…Among these genes, PLCXD3, ARHGAP9 and TCF7L1 have been reported to have potential roles in the therapeutic effect of lithium treatment. 67 In 2019, Han et al described their WES study in 53 patients with bipolar disorder and 82 healthy controls. In the study, they also applied structural MRI data to find variants associated with cortical grey matter thickness and the integrity of white matter.…”

Section: Polygenicity and Polygenic Scoresmentioning

confidence: 99%

Genomic and neuroimaging approaches to bipolar disorder

et al. 2022

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Background To date, besides genome-wide association studies, a variety of other genetic analyses (e.g. polygenic risk scores, whole-exome sequencing and whole-genome sequencing) have been conducted, and a large amount of data has been gathered for investigating the involvement of common, rare and very rare types of DNA sequence variants in bipolar disorder. Also, non-invasive neuroimaging methods can be used to quantify changes in brain structure and function in patients with bipolar disorder. Aims To provide a comprehensive assessment of genetic findings associated with bipolar disorder, based on the evaluation of different genomic approaches and neuroimaging studies. Method We conducted a PubMed search of all relevant literatures from the beginning to the present, by querying related search strings. Results ANK3, CACNA1C, SYNE1, ODZ4 and TRANK1 are five genes that have been replicated as key gene candidates in bipolar disorder pathophysiology, through the investigated studies. The percentage of phenotypic variance explained by the identified variants is small (approximately 4.7%). Bipolar disorder polygenic risk scores are associated with other psychiatric phenotypes. The ENIGMA-BD studies show a replicable pattern of lower cortical thickness, altered white matter integrity and smaller subcortical volumes in bipolar disorder. Conclusions The low amount of explained phenotypic variance highlights the need for further large-scale investigations, especially among non-European populations, to achieve a more complete understanding of the genetic architecture of bipolar disorder and the missing heritability. Combining neuroimaging data with genetic data in large-scale studies might help researchers acquire a better knowledge of the engaged brain regions in bipolar disorder.

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Identification of potential genetic risk factors for bipolar disorder by whole-exome sequencing

Cited by 17 publications

References 42 publications

‘There and Back Again’—Forward Genetics and Reverse Phenotyping in Pulmonary Arterial Hypertension

‘There and Back Again’—Forward Genetics and Reverse Phenotyping in Pulmonary Arterial Hypertension

The PI3K/mTOR Pathway Is Targeted by Rare Germline Variants in Patients with Both Melanoma and Renal Cell Carcinoma

Genomic and neuroimaging approaches to bipolar disorder

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