Genome-wide association study identified INSC gene associated with Trail Making Test Part A and Alzheimer's disease related cognitive phenotypes

Wang, Kesheng; Chun, Xu; Smith, Amanda; Xiao, Danqing; Navia, R Osvaldo; Lu, Yongke; Xie, Changchun; Piamjariyakul, Ubolrat; Initiative, Alzheimer’s Disease Neuroimaging

doi:10.1016/j.pnpbp.2021.110393

Cited by 8 publications

(9 citation statements)

References 71 publications

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“…Variants in SPOCK3 have been associated with verbal declarative memory in a GWAS 46 and variability in cytokine secretion in response to smallpox vaccine 47 . The rs117925493 SNP near INSC that was associated with AD in this study was reported recently as a GWS association with several cognitive traits and a significant expression quantitative trait locus for INSC 48 . NCOA1 has been associated with the amyloid beta (Aβ)42/Aβ40 ratio measured in plasma via a gene‐based test including five rare variants in 370 middle‐aged African American participants of the Atherosclerosis Risk in Communities‐Neurocognitive Study 49 .…”

Section: Discussionsupporting

confidence: 57%

Novel loci for Alzheimer's disease identified by a genome‐wide association study in Ashkenazi Jews

Farrell

Mez

et al. 2023

Alzheimer's & Dementia

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INTRODUCTIONMost Alzheimer's disease (AD) loci have been discovered in individuals with European ancestry (EA).METHODSWe applied principal component analysis using Gaussian mixture models and an Ashkenazi Jewish (AJ) reference genome‐wide association study (GWAS) data set to identify Ashkenazi Jews ascertained in GWAS (n = 42,682), whole genome sequencing (WGS, n = 16,815), and whole exome sequencing (WES, n = 20,504) data sets. The association of AD was tested genome wide (GW) in the GWAS and WGS data sets and exome wide (EW) in all three data sets (EW). Gene‐based analyses were performed using aggregated rare variants.RESULTSIn addition to apolipoprotein E (APOE), GW analyses (1355 cases and 1661 controls) revealed associations with TREM2 R47H (p = 9.66 × 10−9), rs541586606 near RAB3B (p = 5.01 × 10−8), and rs760573036 between SPOCK3 and ANXA10 (p = 6.32 × 10−8). In EW analyses (1504 cases and 2047 controls), study‐wide significant association was observed with rs1003710 near SMAP2 (p = 1.91 × 10−7). A significant gene‐based association was identified with GIPR (p = 7.34 × 10−7).DISCUSSIONOur results highlight the efficacy of founder populations for AD genetic studies.

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Section: Discussionsupporting

confidence: 57%

Novel loci for Alzheimer's disease identified by a genome‐wide association study in Ashkenazi Jews

Farrell

Mez

et al. 2023

Alzheimer's & Dementia

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“…As a type of dementia, AD causes memory loss and cognitive impairment with deficits in executive, language and/or visuospatial functions ( Nikolac Perkovic et al, 2021 ). So far, more than 50 million people around the world have lived with dementia, and approximately 60–80% of them have suffered from the AD ( Wang et al, 2021 ; Fareed et al, 2022 ), which imposes social, psychological and economic burdens on patients ( Andrews et al, 2020 ). It has been reported that genetic factors play an important role in developing the AD, with an estimated heritability being between 58 and 74% ( Roussotte et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

“…Genetically, the ε4 allele of the APOE gene is the strongest risk factor for the AD ( Liu et al, 2013 ). Evidence suggests that heterozygous carriers of an ε4 allele are 3–4 times more likely to develop the AD than noncarriers ( Colovati et al, 2020 ), so GWAS for the AD typically include APOE4 allelic dosage (i.e., the number of ε4 alleles in a subject’s APOE genotype) as a covariate ( Mormino et al, 2016 ; Wang et al, 2021 ; Schneider et al, 2022 ). The EPC2 gene belonging to the polycomb protein family is involved in heterochromatin formation, and chromatin remodeling may play a role in neurodegenerative diseases such as AD ( Kim et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

X chromosome-wide association study of quantitative biomarkers from the Alzheimer’s Disease Neuroimaging Initiative study

Wang,

Yuan,

Zhu

et al. 2023

Front. Aging Neurosci.

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IntroductionAlzheimer’s disease (AD) is a complex neurodegenerative disease with high heritability. Compared to autosomes, a higher proportion of disorder-associated genes on X chromosome are expressed in the brain. However, only a few studies focused on the identification of the susceptibility loci for AD on X chromosome.MethodsUsing the data from the Alzheimer’s Disease Neuroimaging Initiative Study, we conducted an X chromosome-wide association study between 16 AD quantitative biomarkers and 19,692 single nucleotide polymorphisms (SNPs) based on both the cross-sectional and longitudinal studies.ResultsWe identified 15 SNPs statistically significantly associated with different quantitative biomarkers of the AD. For the cross-sectional study, six SNPs (rs5927116, rs4596772, rs5929538, rs2213488, rs5920524, and rs5945306) are located in or near to six genes DMD, TBX22, LOC101928437, TENM1, SPANXN1, and ZFP92, which have been reported to be associated with schizophrenia or neuropsychiatric diseases in literature. For the longitudinal study, four SNPs (rs4829868, rs5931111, rs6540385, and rs763320) are included in or near to two genes RAC1P4 and AFF2, which have been demonstrated to be associated with brain development or intellectual disability in literature, while the functional annotations of other five novel SNPs (rs12157031, rs428303, rs5953487, rs10284107, and rs5955016) have not been found.Discussion15 SNPs were found statistically significantly associated with the quantitative biomarkers of the AD. Follow-up study in molecular genetics is needed to verify whether they are indeed related to AD. The findings in this article expand our understanding of the role of the X chromosome in exploring disease susceptibility, introduce new insights into the molecular genetics behind the AD, and may provide a mechanistic clue to further AD-related studies.

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“…All subjects underwent neuropsychological assessments for different cognitive domains, including auditory verbal learning Test (AVLT), which consists of immediate, cued, and delayed recall and recognition, that reflect verbal working and episode memory [32]; Rey-Osterrieth complex figure test (ROCF), which consists of a copy trial and a recall trial of a complex figure, that reflect visuospatial working and episode memory [33]; digit span test-forward and backward, which tests number storage capacity in working memory [34]; trail making test (TMT) A and B, which reflects executive function, perceptual scanning skills and cognitive flexibility [35]; and Boston naming test (BNT), which reflects language/semantic memory [36].…”

Section: Neuropsychological Assessmentmentioning

confidence: 99%

Shared and unique effects of ApoEε4 and pathogenic gene mutation on cognition and imaging in preclinical familial Alzheimer’s disease

et al. 2023

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Background Neuropsychology and imaging changes have been reported in the preclinical stage of familial Alzheimer’s disease (FAD). This study investigated the effects of APOEε4 and known pathogenic gene mutation on different cognitive domains and circuit imaging markers in preclinical FAD. Methods One hundred thirty-nine asymptomatic subjects in FAD families, including 26 APOEε4 carriers, 17 APP and 20 PS1 mutation carriers, and 76 control subjects, went through a series of neuropsychological tests and MRI scanning. Test scores and imaging measures including volumes, diffusion indices, and functional connectivity (FC) of frontostriatal and hippocampus to posterior cingulate cortex pathways were compared between groups and analyzed for correlation. Results Compared with controls, the APOEε4 group showed increased hippocampal volume and decreased FC of fronto-caudate pathway. The APP group showed increased recall scores in auditory verbal learning test, decreased fiber number, and increased radial diffusivity and FC of frontostriatal pathway. All three genetic groups showed decreased fractional anisotropy of hippocampus to posterior cingulate cortex pathway. These neuropsychological and imaging measures were able to discriminate genetic groups from controls, with areas under the curve from 0.733 to 0.837. Circuit imaging measures are differentially associated with scores in various cognitive scales in control and genetic groups. Conclusions There are neuropsychological and imaging changes in the preclinical stage of FAD, some of which are shared by APOEε4 and known pathogenic gene mutation, while some are unique to different genetic groups. These findings are helpful for the early identification of Alzheimer’s disease and for developing generalized and individualized prevention and intervention strategies.

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Genome-wide association study identified INSC gene associated with Trail Making Test Part A and Alzheimer's disease related cognitive phenotypes

Cited by 8 publications

References 71 publications

Novel loci for Alzheimer's disease identified by a genome‐wide association study in Ashkenazi Jews

Novel loci for Alzheimer's disease identified by a genome‐wide association study in Ashkenazi Jews

X chromosome-wide association study of quantitative biomarkers from the Alzheimer’s Disease Neuroimaging Initiative study

Shared and unique effects of ApoEε4 and pathogenic gene mutation on cognition and imaging in preclinical familial Alzheimer’s disease

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