1.
Insight into susceptibility genes associated with bipolar disorder: a systematic review.
Kalcev, G, Preti, A, Scano, A, Orrù, G, Carta, MG
European review for medical and pharmacological sciences. 2021;(18):5701-5724
Abstract
OBJECTIVE Bipolar disorder (BD) is a severe disorder, and it is associated with an increased risk of mortality. About 25% of patients with BD have attempted and 11% have died by suicide. All these characteristics suggest that the disorders within the bipolar spectrum are a crucial public health problem. With the development of molecular genetics in recent decades, it was possible to more easily detect risk genes associated with this disorder. This study aimed at summarizing the findings of systematic reviews and meta-analyses on the topic and assessing the quality of the available evidence. MATERIALS AND METHODS PubMed/Medline and Web of Science were searched to identify systematic reviews and meta-analyses published during 2013-2019. Standard methodology was applied to synthesize and assess the retrieved literature. RESULTS This systematic review identifies a number of potential risk genes associated with bipolar disorder whose mechanism of action has yet to be confirmed. They are divided into several groups: 1) a list of the most significant susceptibility genetic factors associated with BD; 2) the implication of the ZNF804A gene in BD; 3) the role of genes involved in calcium signaling in BD; 4) DNA methylation in BD; 5) BD and risk suicide genes; 6) susceptibility genes for early-onset BD; 7) candidate genes common to both BD and schizophrenia; 8) genes involved in cognitive status in BD cases; 9) genes involved in structural alteration in BD brain tissue; 10) genes involved in lithium response in BD. CONCLUSIONS Future research should concentrate on molecular mechanisms by which genetic variants play a major role in BD. Supplemental research is needed to replicate the applicable results.
2.
Genetic Variation in the SLC8A1 Calcium Signaling Pathway Is Associated With Susceptibility to Kawasaki Disease and Coronary Artery Abnormalities.
Shimizu, C, Eleftherohorinou, H, Wright, VJ, Kim, J, Alphonse, MP, Perry, JC, Cimaz, R, Burgner, D, Dahdah, N, Hoang, LT, et al
Circulation. Cardiovascular genetics. 2016;(6):559-568
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Abstract
BACKGROUND Kawasaki disease (KD) is an acute pediatric vasculitis in which host genetics influence both susceptibility to KD and the formation of coronary artery aneurysms. Variants discovered by genome-wide association studies and linkage studies only partially explain the influence of genetics on KD susceptibility. METHODS AND RESULTS To search for additional functional genetic variation, we performed pathway and gene stability analysis on a genome-wide association study data set. Pathway analysis using European genome-wide association study data identified 100 significantly associated pathways (P<5×10-4). Gene stability selection identified 116 single nucleotide polymorphisms in 26 genes that were responsible for driving the pathway associations, and gene ontology analysis demonstrated enrichment for calcium transport (P=1.05×10-4). Three single nucleotide polymorphisms in solute carrier family 8, member 1 (SLC8A1), a sodium/calcium exchanger encoding NCX1, were validated in an independent Japanese genome-wide association study data set (meta-analysis P=0.0001). Patients homozygous for the A (risk) allele of rs13017968 had higher rates of coronary artery abnormalities (P=0.029). NCX1, the protein encoded by SLC8A1, was expressed in spindle-shaped and inflammatory cells in the aneurysm wall. Increased intracellular calcium mobilization was observed in B cell lines from healthy controls carrying the risk allele. CONCLUSIONS Pathway-based association analysis followed by gene stability selection proved to be a valuable tool for identifying risk alleles in a rare disease with complex genetics. The role of SLC8A1 polymorphisms in altering calcium flux in cells that mediate coronary artery damage in KD suggests that this pathway may be a therapeutic target and supports the study of calcineurin inhibitors in acute KD.