Genome-wide pathway analysis implicates intracellular transmembrane protein transport in Alzheimer disease

Hong, Mun‐Gwan; Alexeyenko, Andrey; Lambert, Jean‐Charles; Amouyel, Philippe; Prince, Jonathan A.

doi:10.1038/jhg.2010.92

Cited by 46 publications

(50 citation statements)

References 17 publications

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“…Previous Results from Pathway Analysis of AD GWAS Prior to this study, six pathway analyses of AD GWAS have been reported with five studies using the KEGG database [4][5][6][7][8][9]. We compared our findings with the previous pathway analyses of AD GWAS.…”

Section: Two Ad Brain Expression Gwas Datasetsmentioning

confidence: 76%

“…We compared our findings with the previous pathway analyses of AD GWAS. All of the pathway analysis results were publicly available from the original studies [4][5][6][7][8][9].…”

Section: Two Ad Brain Expression Gwas Datasetsmentioning

confidence: 99%

“…A large proportion of AD heritability has yet to be explained. Fortunately, the existing large-scale GWAS datasets provide strong support for the investigation of AD mechanisms using pathway analysis methods [4][5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

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Integrating Genome-Wide Association Study and Brain Expression Data Highlights Cell Adhesion Molecules and Purine Metabolism in Alzheimer’s Disease

Zhang

Liao

et al. 2014

Mol Neurobiol

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Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly. Recently, genome-wide association studies (GWAS) have been used to investigate AD pathogenesis. However, a large proportion of AD heritability has yet to be explained. We previously identified the cell adhesion molecule (CAM) pathway as a consistent signal in two AD GWAS. However, it is unclear whether CAM is present in the Genetic and Environmental Risk for Alzheimer's Disease Consortium (GERAD) GWAS and brain expression GWAS. Meanwhile, we think integrating AD GWAS and AD brain expression datasets may provide complementary information to identify important pathways involved in AD. Here, we conducted a systems analysis using (1) KEGG pathways, (2) large-scale AD GWAS from GERAD (n = 11,789), (3) two brain expression GWAS datasets (n = 399) from the AD cerebellum and temporal cortex, and (4) previous results from pathway analysis of AD GWAS. Our results indicate that (1) CAM is a consistent signal in five AD GWAS; (2) CAM is the most significant signal in AD; (3) we confirmed previous AD risk pathways related to immune system and diseases, and cardiovascular disease, etc.; and (4) we highlighted the purine metabolism pathway in AD for the first time. We believe that our results may advance our understanding of AD mechanisms and will be very informative for future genetic studies in AD.

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Section: Two Ad Brain Expression Gwas Datasetsmentioning

confidence: 76%

“…We compared our findings with the previous pathway analyses of AD GWAS. All of the pathway analysis results were publicly available from the original studies [4][5][6][7][8][9].…”

Section: Two Ad Brain Expression Gwas Datasetsmentioning

confidence: 99%

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Integrating Genome-Wide Association Study and Brain Expression Data Highlights Cell Adhesion Molecules and Purine Metabolism in Alzheimer’s Disease

Zhang

Liao

et al. 2014

Mol Neurobiol

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“…Mitochondrial dysfunction has been associated with several pathological processes in AD, such as brain hypometabolism, synaptic pathology, accumulation of APP, and Aβ influx to the cell [14][15][16]. Damaged mitochondria exert a specific influence on the AD pathophysiology through interplay with Aβ and its precursor, AβPP.…”

Section: Tomm40mentioning

confidence: 99%

Biomarkers for the early diagnosis of Alzheimer’s disease: The challenge of XXI century

Contino¹,

Cantore²,

Leopoldo³

et al. 2013

AAD

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AD is the most common form of dementia among the aging population. The neuropathological alterations of AD are represented by the neurofibrillary tangles and extracellular amyloid plaques formation. These two hallmarks are routinely used as biomarkers for AD diagnosis and can allow the identification of the pathology in a late phase. The urgent need to develop probes for PET analysis that can be used in an early diagnosis of this disorder opened a new scenario in which new biomarkers involved in the first step of AD can be easily detected. Recently, an increasing number of studies indicated as new biomarkers P-gp, TLR4, MIR and free serum copper that are involved in the onset of AD. It has been extensively reported that a P-gp dysfunction in brain can be considered one of the causes of the AD accumulation in brain parenchyma and that the up-regulation of inflammatory gene expression and inflammatory signaling due to MIR and TLR4 modulated the development and the progression of AD.

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“…Both the apolipoprotein E (APOE) gene and the TOMM40-APOE locus, tagged by rs2075650 in the translocase of outer mitochondrial membrane 40 (TOMM40) gene (see Supplementary Information), have been implicated (Hong et al, 2010;Li et al, 2008;Schiepers et al, 2011). Investigations of depression have also indicated that the APOE e4 risk allele influences both the onset and risk for late-life depression (Butters et al, 2003;Yen et al, 2007) and has been associated with gray matter reductions (Cherbuin et al, 2007), reduced white matter integrity (Heise et al, 2011) and cognitive impairment (Greenwood et al, 2000) in healthy adults, further suggesting that genetic mechanisms associated with dementia may contribute to the development of mood disorder.…”

Section: Introductionmentioning

confidence: 99%

TOMM40 rs2075650 May Represent a New Candidate Gene for Vulnerability to Major Depressive Disorder

McFarquhar

Elliott

McKie

et al. 2014

Neuropsychopharmacol

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Evidence suggests that depression is a risk factor for dementia; however, the relationship between the two conditions is not fully understood. A novel gene (TOMM40) has been consistently associated with Alzheimer's disease (AD), but has received no attention in depression. We conducted a three-level cross-sectional study to investigate the association of the TOMM40 rs2075650 SNP with depression. We recruited a community sample of 1220 participants (571 controls, 649 lifetime depression) to complete a psychiatric background questionnaire, the Brief Symptom Inventory, and Big Five Inventory at Level-1, 243 (102 controls, 97 remitted, 44 currently depressed) to complete a face-toface clinical interview and neuropsychological testing at Level-2 and 58 (33 controls, 25 remitted) to complete an emotional face-processing task during fMRI at Level-3. Our results indicated that the TOMM40 rs2075650 G allele was a significant risk factor for lifetime depression (p ¼ 0.00006) and, in depressed subjects, was a significant predictor of low extraversion (p ¼ 0.009). Currently depressed risk allele carriers showed subtle executive dysfunction (p ¼ 0.004) and decreased positive memory bias (p ¼ 0.021) together with reduced activity in the posterior (p (FWE) ¼ 0.045) and anterior (p (FWE) ¼ 0.041) cingulate during sad face emotion processing. Our results suggest that TOMM40 rs2075650 may be a risk factor for the development of depression characterized by reduced extraversion, impaired executive function, and decreased positive emotional recall, and reduced top-down cortical control during sad emotion processing.

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Genome-wide pathway analysis implicates intracellular transmembrane protein transport in Alzheimer disease

Cited by 46 publications

References 17 publications

Integrating Genome-Wide Association Study and Brain Expression Data Highlights Cell Adhesion Molecules and Purine Metabolism in Alzheimer’s Disease

Integrating Genome-Wide Association Study and Brain Expression Data Highlights Cell Adhesion Molecules and Purine Metabolism in Alzheimer’s Disease

Biomarkers for the early diagnosis of Alzheimer’s disease: The challenge of XXI century

TOMM40 rs2075650 May Represent a New Candidate Gene for Vulnerability to Major Depressive Disorder

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