Ditching candidate gene association studies: lessons from psychiatric genetics

Duarte, Rodrigo R.R.; Brentani, Helena; Powell, Timothy R.

doi:10.1590/1516-4446-2020-1646

Cited by 4 publications

(4 citation statements)

References 5 publications

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“…This genome-wide characterization of HIV-1 acquisition was needed considering the high h 2 SNP estimated for this trait using the LD score regression method, which disregards SNPs located at the MHC to avoid inflated estimates ( Bulik-Sullivan et al., 2015b ). Thus, our study represents an important step toward a better understanding of the risk genes involved in HIV-1 acquisition, beyond those explored due to historical relevance alone, which could reveal genuine mechanisms associated with susceptibility, identified through hypothesis-free analyses, as observed in other fields (e.g., psychiatry, see Duarte et al., 2021 ).…”

Section: Discussionmentioning

confidence: 94%

Transcriptome-wide association study of HIV-1 acquisition identifies HERC1 as a susceptibility gene

et al. 2022

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Section: Discussionmentioning

confidence: 94%

Transcriptome-wide association study of HIV-1 acquisition identifies HERC1 as a susceptibility gene

et al. 2022

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“…With the advancements of gene detection technology, there is promise of better elucidation of the underlying genetic architecture of TRS and clozapine resistance. Following the cost reduction in new genotyping technology, it has been pointed out that psychiatric genetics is shifting away from candidate association studies based on historical choices [ 179 ]. Genome-wide association studies (GWAS) adopt an atheoretical approach, have improved our understanding of the genetic basis of schizophrenia and other psychiatric disorders [ 57 , 180 ], and have the potential to examine common genetic variants related to TRS [ 181 ].…”

Section: Discussionmentioning

confidence: 99%

Treatment-Resistant Schizophrenia, Clozapine Resistance, Genetic Associations, and Implications for Precision Psychiatry: A Scoping Review

Ying

Chew

McIntyre

et al. 2023

Genes

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Treatment-resistant schizophrenia (TRS) is often associated with severe burden of disease, poor quality of life and functional impairment. Clozapine is the gold standard for the treatment of TRS, although it is also known to cause significant side effects in some patients. In view of the burgeoning interest in the role of genetic factors in precision psychiatry, we conducted a scoping review to narratively summarize the current genetic factors associated with TRS, clozapine resistance and side effects to clozapine treatment. We searched PubMed from inception to December 2022 and included 104 relevant studies in this review. Extant evidence comprised associations between TRS and clozapine resistance with genetic factors related to mainly dopaminergic and serotoninergic neurotransmitter systems, specifically, TRS and rs4680, rs4818 within COMT, and rs1799978 within DRD2; clozapine resistance and DRD3 polymorphisms, CYP1A2 polymorphisms; weight gain with LEP and SNAP-25 genes; and agranulocytosis risk with HLA-related polymorphisms. Future studies, including replication in larger multi-site samples, are still needed to elucidate putative risk genes and the interactions between different genes and their correlations with relevant clinical factors such as psychopathology, psychosocial functioning, cognition and progressive changes with treatment over time in TRS and clozapine resistance.

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“…These genes implicate hypothalamic–pituitary–adrenal (HPA) axis dysfunction, glucocorticoid dysregulation, and immune system abnormalities in PTSD. However, a candidate gene approach is not suitable to PTSD due to the complex nature of the disorder, especially since now there can be hundreds of genes associated with psychiatric traits (Duarte et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…However, a candidate gene approach is not suitable to PTSD due to the complex nature of the disorder, especially since now there can be hundreds of genes associated with psychiatric traits (Duarte et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Identifying genetic loci that are associated with changes in gene expression in PTSD in a South African cohort

Swart

Plessis

Rust

et al. 2023

Journal of Neurochemistry

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The molecular mechanisms underlying posttraumatic stress disorder (PTSD) are yet to be fully elucidated, especially in underrepresented population groups. Expression quantitative trait loci (eQTLs) are DNA sequence variants that influence gene expression, in a local (cis‐) or distal (trans‐) manner, and subsequently impact cellular, tissue, and system physiology. This study aims to identify genetic loci associated with gene expression changes in a South African PTSD cohort. Genome‐wide genotype and RNA‐sequencing data were obtained from 32 trauma‐exposed controls and 35 PTSD cases of mixed‐ancestry, as part of the SHARED ROOTS project. The first approach utilised 108 937 single‐nucleotide polymorphisms (SNPs) (MAF > 10%) and 11 312 genes with Matrix eQTL to map potential eQTLs, while controlling for covariates as appropriate. The second analysis was focused on 5638 SNPs related to a previously calculated PTSD polygenic risk score for this cohort. SNP‐gene pairs were considered eQTLs if they surpassed Bonferroni correction and had a false discovery rate <0.05. We did not identify eQTLs that significantly influenced gene expression in a PTSD‐dependent manner. However, several known cis‐eQTLs, independent of PTSD diagnosis, were observed. rs8521 (C > T) was associated with TAGLN and SIDT2 expression, and rs11085906 (C > T) was associated with ZNF333 expression. This exploratory study provides insight into the molecular mechanisms associated with PTSD in a non‐European, admixed sample population. This study was limited by the cross‐sectional design and insufficient statistical power. Overall, this study should encourage further multi‐omics approaches towards investigating PTSD in diverse populations.image

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Ditching candidate gene association studies: lessons from psychiatric genetics

Cited by 4 publications

References 5 publications

Transcriptome-wide association study of HIV-1 acquisition identifies HERC1 as a susceptibility gene

Transcriptome-wide association study of HIV-1 acquisition identifies HERC1 as a susceptibility gene

Treatment-Resistant Schizophrenia, Clozapine Resistance, Genetic Associations, and Implications for Precision Psychiatry: A Scoping Review

Identifying genetic loci that are associated with changes in gene expression in PTSD in a South African cohort

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