Large‐scale whole‐exome sequencing association study identifies <i>FOXH1</i> gene and sphingolipid metabolism pathway influencing major depressive disorder

Zhou, Wei; Chen, Luan; Jiang, Bixuan; Sun, Yifeng; Li, M; Wu, Hao; Zhang, Na; Sun, Xiaofang; Qin, Shengying

doi:10.1111/cns.13733

Cited by 8 publications

(6 citation statements)

References 11 publications

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“…Advancement in NGS technology can help identify rare variants [ 18 ]. Previous studies have conducted gene-based analyses of rare damaging variants to identify genes related to MDD using the UK Biobank exome dataset [ 19 , 20 ]. Zhou et al revealed that genes based on rare variants, including FOXO1 , MAPK10 , DLGAP3 , ARID5B , ASXL2 , and MED13 , were significantly associated with MDD [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies have conducted gene-based analyses of rare damaging variants to identify genes related to MDD using the UK Biobank exome dataset [ 19 , 20 ]. Zhou et al revealed that genes based on rare variants, including FOXO1 , MAPK10 , DLGAP3 , ARID5B , ASXL2 , and MED13 , were significantly associated with MDD [ 19 ]. Cheng et al performed a gene-based burden test to identify OR8B4 , TRAPPC11 , SBK3 , and TNRC6B between patients with MDD with high polygenic risk scores (PRS) and those with low PRS [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

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Integration of whole-exome sequencing and structural neuroimaging analysis in major depressive disorder: a joint study

Oh,

Han,

Kim

et al. 2024

Transl Psychiatry

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Major depressive disorder (MDD) is a common mental illness worldwide and is triggered by an intricate interplay between environmental and genetic factors. Although there are several studies on common variants in MDD, studies on rare variants are relatively limited. In addition, few studies have examined the genetic contributions to neurostructural alterations in MDD using whole-exome sequencing (WES). We performed WES in 367 patients with MDD and 161 healthy controls (HCs) to detect germline and copy number variations in the Korean population. Gene-based rare variants were analyzed to investigate the association between the genes and individuals, followed by neuroimaging-genetic analysis to explore the neural mechanisms underlying the genetic impact in 234 patients with MDD and 135 HCs using diffusion tensor imaging data. We identified 40 MDD-related genes and observed 95 recurrent regions of copy number variations. We also discovered a novel gene, FRMPD3, carrying rare variants that influence MDD. In addition, the single nucleotide polymorphism rs771995197 in the MUC6 gene was significantly associated with the integrity of widespread white matter tracts. Moreover, we identified 918 rare exonic missense variants in genes associated with MDD susceptibility. We postulate that rare variants of FRMPD3 may contribute significantly to MDD, with a mild penetration effect.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Integration of whole-exome sequencing and structural neuroimaging analysis in major depressive disorder: a joint study

Oh,

Han,

Kim

et al. 2024

Transl Psychiatry

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“…Several previous genome-wide association studies (GWAS) have identified common variations related to MDD. However, the estimated heritability of these common genetic mutations ranges from only 9 to 10% ( 4 ). Thus, researchers have shifted their attention to other undiscovered heritability, such as rare gene variations (MAF < 0.5%) and copy number variations (CNVs).…”

Section: Introductionmentioning

confidence: 99%

“…The authors identified 1,985 variations in 479 MDD-related genes using different approaches and databases, reporting 14 gene mutations that differed between patients with MDD and the general South Asian population ( 6 ). A recent study that utilized 16,702 samples from the UK Biobank also highlighted the FOXH1 gene and sphingolipid metabolism pathways as the most significant pathogenic genes for MDD ( 4 ). Despite several advances in understanding the genetic mutations underlying MDD, studies are still scarce and have limitations such as small sample sizes and large numbers of Europeans.…”

Section: Introductionmentioning

confidence: 99%

Genetic variations in the retrograde endocannabinoid signaling pathway in Chinese patients with major depressive disorder

Gong

et al. 2023

Front. Neurol.

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BackgroundThe retrograde endocannabinoid (eCB) pathway is closely associated with the etiology of major depressive disorder (MDD) at both pathophysiological and genetic levels. This study aimed to investigate the potential role of genetic mutations in the eCB pathway and underlying mechanisms in Han Chinese patients with MDD.MethodsA total of 96 drug-naïve patients with first-episode MDD and 62 healthy controls (HCs) were recruited. Whole-exome sequencing was performed to identify the gene mutation profiles in patients with MDD. Results were filtered to focus on low-frequency variants and rare mutations (minor allele frequencies <0.05) related to depressive phenotypes. Enrichment analyses were performed for 146 selected genes to examine the pathways in which the most significant enrichment occurred. A protein–protein interaction (PPI) network analysis was performed to explore the biological functions of the eCB pathway. Finally, based on current literature, a preliminary analysis was conducted to explore the effect of genetic mutations on the function of this pathway.ResultsOur analysis identified 146 (15.02%) depression-related genetic mutations in patients with MDD when compared with HCs, and 37 of the mutations were enriched in the retrograde eCB signaling pathway. Seven hub genes in the eCB pathway were closely related to mitochondrial function, including Complex I genes (NDUFS4, NDUFV2, NDUFA2, NDUFA12, NDUFB11) and genes associated with protein (PARK7) and enzyme (DLD) function in the regulation of mitochondrial oxidative stress.ConclusionThese results indicate that genetic mutations in the retrograde eCB pathway represent potential etiological factors associated with the pathogenesis of MDD.

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“…Previous studies have conducted gene-based analyses of rare damaging variants to identify genes related to MDD using the UK Biobank exome dataset [9,10]. Zhou et al revealed that genes based on rare variants, including FOXO1, MAPK10, DLGAP3, ARID5B, ASXL2, and MED13, were signi cantly associated with MDD [9]. Cheng et al performed a gene-based burden test to identify OR8B4, TRAPPC11, SBK3, and TNRC6B between patients with MDD with high polygenic risk scores (PRS) and those with low PRS [10].…”

Section: Introductionmentioning

confidence: 99%

Integration of Whole-Exome Sequencing and Structural Neuroimaging Analysis in Major Depressive Disorder: A Joint Study

Ham,

Oh,

Han

et al. 2023

Preprint

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Major depressive disorder (MDD) is a common mental illness worldwide and is triggered by an intricate interplay between environmental and genetic factors. Although there are several studies on common variants in MDD, studies on rare variants are relatively limited. In addition, few studies have examined the genetic contributions to neurostructural alterations in MDD using whole-exome sequencing (WES). We performed WES in 367 patients with MDD and 161 healthy controls (HCs) to detect germline and copy number variations. Gene-based rare variants were analyzed to investigate the association between genes and individuals, followed by neuroimaging-genetic analysis to explore the neural mechanisms underlying the genetic impact in 234 patients with MDD and 135 HCs using diffusion tensor imaging data. We identified 40 MDD-related genes and observed 95 recurrent regions of copy number variations. We also discovered a novel gene, FRMPD3, carrying rare variants that influence MDD. In addition, the single nucleotide polymorphism rs771995197 in the MUC6 gene was significantly associated with the integrity of widespread white matter tracts. Moreover, we identified 918 rare exonic missense variants in genes associated with MDD susceptibility. We postulate that rare variants of FRMPD3 may contribute significantly to MDD, with a mild penetration effect.

show abstract

Large‐scale whole‐exome sequencing association study identifies FOXH1 gene and sphingolipid metabolism pathway influencing major depressive disorder

Cited by 8 publications

References 11 publications

Integration of whole-exome sequencing and structural neuroimaging analysis in major depressive disorder: a joint study

Integration of whole-exome sequencing and structural neuroimaging analysis in major depressive disorder: a joint study

Genetic variations in the retrograde endocannabinoid signaling pathway in Chinese patients with major depressive disorder

Integration of Whole-Exome Sequencing and Structural Neuroimaging Analysis in Major Depressive Disorder: A Joint Study

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