Genome-wide association identifies genetic variants associated with lentiform nucleus volume in N = 1345 young and elderly subjects

Hibar, Derrek P.; Stein, Jason L.; Ryles, April B.; Kohannim, Omid; Jahanshad, Neda; Medland, Sarah E.; Hansell, Narelle K.; McMahon, Katie L.; Zubicaray, Greig I. de; Montgomery, Grant W.; Martin, Nicholas G.; Wright, Margaret J.; Saykin, Andrew J.; Jack, Clifford R.; Weiner, Michael W.; Toga, Arthur W.; Thompson, Paul M.

doi:10.1007/s11682-012-9199-7

Cited by 29 publications

(23 citation statements)

References 57 publications

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“…The population cohorts were the Older Australian Twins Study (OATS; Sachdev et al, 2011), the Sydney Memory and Ageing Study (MAS; Brodaty et al, 2012), and the Queensland Twin Imaging (QTIM) cohort, of which the latter consists of young adults (Hibar et al, 2013). For Sydney MAS and OATS, diagnosis of MCI and AD were made with the most recent consensus criteria (Winblad et al, 2004).…”

Section: Methodsmentioning

confidence: 99%

The effect of increased genetic risk for Alzheimer's disease on hippocampal and amygdala volume

Lupton

Strike

Hansell

et al. 2016

Neurobiology of Aging

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109

107

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Reduction in hippocampal and amygdala volume measured via structural magnetic resonance imaging is an early marker of Alzheimer’s disease (AD). Whether genetic risk factors for AD exert an effect on these subcortical structures independent of clinical status has not been fully investigated. We examine whether increased genetic risk for AD influences hippocampal and amygdala volumes in case-control and population cohorts at different ages, in 1674 older (aged >53 years; 17% AD, 39% mild cognitive impairment [MCI]) and 467 young (16–30 years) adults. An AD polygenic risk score combining common risk variants excluding apolipoprotein E (APOE), and a single nucleotide polymorphism in TREM2, were both associated with reduced hippocampal volume in healthy older adults and those with MCI. APOE ɛ4 was associated with hippocampal and amygdala volume in those with AD and MCI but was not associated in healthy older adults. No associations were found in young adults. Genetic risk for AD affects the hippocampus before the clinical symptoms of AD, reflecting a neurodegenerative effect before clinical manifestations in older adults.

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Section: Methodsmentioning

confidence: 99%

The effect of increased genetic risk for Alzheimer's disease on hippocampal and amygdala volume

Lupton

Strike

Hansell

et al. 2016

Neurobiology of Aging

Self Cite

109

107

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“…The ADNI cohort was also used in 2 GWAS, one identifying SNPs associated with variability in the surface of the visual cortex [317] and the other determining that circadian clock SNPs are not associated with the breakdown of sleep-wake consolidation observed in AD [318]. Hibar et al [541] used ADNI genetic data to perform a GWAS to discover common genetic variants associated with lentiform nucleus volume, implicated in disorders such as Parkinson’s disease, ADHD, and schizophrenia. They identified variants within the flavin-containing monooxygenase gene cluster.…”

Section: Identification Of Genetic Risk Factors For Admentioning

confidence: 99%

2014 Update of the Alzheimer's Disease Neuroimaging Initiative: A review of papers published since its inception

Weiner

Veitch

Aisen

et al. 2015

Alzheimer's & Dementia

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The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer’s disease (AD). The initial study, ADNI-1, enrolled 400 subjects with early mild cognitive impairment (MCI), 200 with early AD, and 200 cognitively normal elderly controls. ADNI-1 was extended by a 2-year Grand Opportunities grant in 2009 and by a competitive renewal, ADNI-2, which enrolled an additional 550 participants and will run until 2015. This article reviews all papers published since the inception of the initiative and summarizes the results to the end of 2013. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are largely consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimer’s Dis 2006;9(Suppl 3):151–3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers select and combine optimum features from multiple modalities, including MRI, [18F]-fluorodeoxyglucose-PET, amyloid PET, CSF biomarkers, and clinical tests; (4) the development of blood biomarkers for AD as potentially noninvasive and low-cost alternatives to CSF biomarkers for AD diagnosis and the assessment of α-syn as an additional biomarker; (5) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects and are leading candidates for the detection of AD in its preclinical stages; (6) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Multimodal methods incorporating APOE status and longitudinal MRI proved most highly predictive of future decline. Refinements of clinical tests used as outcome measures such as clinical dementia rating-sum of boxes further reduced sample sizes; (7) the pioneering of genome-wide association studies that leverage quantitative imaging and biomarker phenotypes, including longitudinal data, to confirm recently identified loci, CR1, CLU, and PICALM and to identify novel AD risk loci; (8) worldwide impact through the establishment of ADNI-like programs in Japan, Australia, Argentina, Taiwan, China, Korea, Europe, and Italy; (9) understanding ...

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“…The role of FMOs in other neurodegenerative diseases is also intriguing but largely correlative. The FMO gene cluster containing FMO1-4 is associated with lentiform nucleus volume, a physiological marker associated with PD, schizophrenia, and other neurological disorders (63). Additionally, hFMO1 and Parkin are down-regulated in a rotenone model of PD carried out in cell culture (64).…”

Section: Neurodegeneration and Neurological Diseasementioning

confidence: 99%

Flavin-containing monooxygenases in aging and disease: Emerging roles for ancient enzymes

Rossner

Kaeberlein

Leiser

2017

Journal of Biological Chemistry

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Edited by F. Peter GuengerichFlavin-containing monooxygenases (FMOs) are primarily studied as xenobiotic metabolizing enzymes with a prominent role in drug metabolism. In contrast, endogenous functions and substrates of FMOs are less well understood. A growing body of recent evidence, however, implicates FMOs in aging, several diseases, and metabolic pathways. The evidence suggests an important role for these well-conserved proteins in multiple processes and raises questions about the endogenous substrate(s) and regulation of FMOs. Here, we present an overview of evidence for FMOs' involvement in aging and disease, discussing the biological context and arguing for increased investigation into the function of these enzymes.

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Genome-wide association identifies genetic variants associated with lentiform nucleus volume in N = 1345 young and elderly subjects

Cited by 29 publications

References 57 publications

The effect of increased genetic risk for Alzheimer's disease on hippocampal and amygdala volume

The effect of increased genetic risk for Alzheimer's disease on hippocampal and amygdala volume

2014 Update of the Alzheimer's Disease Neuroimaging Initiative: A review of papers published since its inception

Flavin-containing monooxygenases in aging and disease: Emerging roles for ancient enzymes

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