A Scan of Chromosome 10 Identifies a Novel Locus Showing Strong Association with Late-Onset Alzheimer Disease

Grupe, Andrew; Li, Yonghong; Rowland, Charles M.; Nowotny, Petra; Hinrichs, Anthony L.; Smemo, Scott; Kauwe, John; Maxwell, Taylor J.; Cherny, Sara; Doil, Lisa; Tacey, Kristina; Luchene, Ryan van; Myers, Amanda; Vrièze, Fabienne Wavrant‐De; Kaleem, Mona; Hollingworth, Paul; Jehu, Luke; Foy, Catherine; Archer, Nicola; Hamilton, Gillian; Holmans, Peter Alan; Morris, Chris M.; Catanese, Joseph J.; Sninsky, John J.; White, Thomas J.; Powell, John; Hardy, John; O'Donovan, Michael Conlon; Lovestone, Simon; Jones, Lesley; Morris, John C.; Thal, Leon J.; Williams, Julie; Goate, Alison M.

doi:10.1086/498851

Cited by 146 publications

(104 citation statements)

References 38 publications

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“…41 SNP rs2576037 in KATNAL2, which has been linked to Conscientiousness in a meta-analysis of GWA, 17 was not associated with this trait in our study (P ¼ 0.395).…”

Section: Genetic Variants Influencing Personalitycontrasting

confidence: 65%

Genome-wide association study of the five-factor model of personality in young Korean women

et al. 2013

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Personality is a determinant of behavior and lifestyle associated with health and human diseases. Although personality is known to be a heritable trait, its polygenic nature has made the identification of genetic variants elusive. We performed a genome-wide association study on 1089 Korean women aged 18-40 years whose personality traits were measured with the Revised NEO Personality Inventory for the five-factor model of personality. To reduce environmental factors that may influence personality traits, this study was restricted to young adult women. In the discovery phase, we identified variants of PTPRD (protein tyrosine phosphatase, receptor type D) that associated this gene with the Openness domain. Other genes that were previously reported to be associated with neurological phenotypes were also associated with personality traits. In particular, DRD1 and ORIA2 were linked to Neuroticism, NKAIN2 with Extraversion, HTR5A with Openness and DRD3 with Agreeableness. Data from our replication study of 2090 subjects confirmed the association between ORIA2 and Neuroticism. We first identified and confirmed a novel region on ORIA2 associated with Neuroticism. Candidate genes for psychiatric disorders were also enriched. These findings contribute to our understanding of the genetic architecture of personality traits and provide critical clues to the neurobiological mechanisms that influence them.

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“…41 SNP rs2576037 in KATNAL2, which has been linked to Conscientiousness in a meta-analysis of GWA, 17 was not associated with this trait in our study (P ¼ 0.395).…”

Section: Genetic Variants Influencing Personalitycontrasting

confidence: 65%

Genome-wide association study of the five-factor model of personality in young Korean women

et al. 2013

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“…The samples were elderly nondemented controls collected by the WUADRC. The dementia screen in these controls has been described elsewhere [Grupe et al, 2006].…”

Section: Control Samplesmentioning

confidence: 99%

Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia

et al. 2008

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Frontotemporal dementia (FTD) is a clinical term encompassing dementia characterized by the presence of two major phenotypes: 1) behavioral and personality disorder, and 2) language disorder, which includes primary progressive aphasia and semantic dementia. Recently, the gene for familial frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U) linked to chromosome 17 was cloned. In the present study, 62 unrelated patients from the Washington University Alzheimer's Disease Research Center and the Midwest Consortium for FTD with clinically diagnosed FTD and/or neuropathologically characterized cases of FTLD-U with or without motor neuron disease (MND) were screened for mutations in the progranulin gene (GRN; also PGRN). We discovered two pathogenic mutations in four families: 1) a single-base substitution within the 3′ splice acceptor site of intron 6/exon 7 (g.5913A>G [IVS6-2A>G]) causing skipping of exon 7 and premature termination of the coding sequence (PTC); and 2) a missense mutation in exon 1 (g.4068C>A) introducing a charged amino acid in the hydrophobic core of the signal peptide at residue 9 (p.A9D). Functional analysis in mutation carriers for the splice acceptor site mutation revealed a 50% decrease in GRN mRNA and protein levels, supporting haploinsufficiency. In contrast, there was no significant difference in the total GRN mRNA between cases and controls NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript carrying the p.A9D mutation. Further, subcellular fractionation and confocal microscopy indicate that although the mutant protein is expressed, it is not secreted, and appears to be trapped within an intracellular compartment, possibly resulting in a functional haploinsufficiency.

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“…Although significant associations with several biological candidate genes, such as PFKFB3, on chromosome 10 have been reported, these findings have not been consistently replicated, and they remain controversial (Grupe et al, 2006). Increased expression of HIF-1α, as well as its target genes, VEGF, and PFKFB3 in both major depressive and bipolar disorder patients have been found in a depressive state compared to healthy control subjects.…”

Section: Neuronal Diseasesmentioning

confidence: 99%

PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3)

Novellasdemunt¹,

Navarro-Sabaté²,

Manzano³

et al. 2013

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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A Scan of Chromosome 10 Identifies a Novel Locus Showing Strong Association with Late-Onset Alzheimer Disease

Cited by 146 publications

References 38 publications

Genome-wide association study of the five-factor model of personality in young Korean women

Genome-wide association study of the five-factor model of personality in young Korean women

Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia

PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3)

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