Serum cholesterol and variant in cholesterol-related gene CETP predict white matter microstructure

Warstadt, Nicholus M.; Dennis, Emily L.; Jahanshad, Neda; Kohannim, Omid; Nir, Talia M.; McMahon, Katie L.; Zubicaray, Greig I. de; Montgomery, Grant W.; Henders, Anjali K.; Martin, Nicholas G.; Whitfield, John B.; Jack, Clifford R.; Bernstein, Matt A.; Weiner, Michael W.; Toga, Arthur W.; Wright, Margaret J.; Thompson, Paul M.

doi:10.1016/j.neurobiolaging.2014.05.024

Cited by 30 publications

(31 citation statements)

References 85 publications

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“…To our knowledge this is the first paper to report an association between an obesity-related gene and white matter (WM) integrity. A recent paper by our group used this approach to find associations between WM and serum cholesterol and cholesterol-related SNPs (Warstadt et al, in press). …”

Section: Discussionmentioning

confidence: 99%

Obesity gene NEGR1 associated with white matter integrity in healthy young adults

et al. 2014

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Obesity is a crucial public health issue in developed countries, with implications for cardiovascular and brain health as we age. A number of commonly-carried genetic variants are associated with obesity. Here we aim to see whether variants in obesity-associated genes - NEGR1, FTO, MTCH2, MC4R, LRRN6C, MAP2K5, FAIM2, SEC16B, ETV5, BDNF-AS, ATXN2L, ATP2A1, KCTD15, and TNN13K - are associated with white matter microstructural properties, assessed by high angular resolution diffusion imaging (HARDI) in young healthy adults between 20–30 years of age from the Queensland Twin Imaging study (QTIM). We began with a multi-locus approach testing how a number of common genetic risk factors for obesity at the single nucleotide polymorphism (SNP) level may jointly influence white matter integrity throughout the brain and found a wide spread genetic effect. Risk allele rs2815752 in NEGR1 was most associated with lower white matter integrity across a substantial portion of the brain. Across the area of significance in the bilateral posterior corona radiata, each additional copy of the risk allele was associated with a 2.2% lower average FA. This is the first study to find an association between an obesity risk gene and differences in white matter integrity. As our subjects were young and healthy, our results suggest that NEGR1 has effects on brain structure independent of its effect on obesity.

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Section: Discussionmentioning

confidence: 99%

Obesity gene NEGR1 associated with white matter integrity in healthy young adults

et al. 2014

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“…Warstadt et al [179] found evidence that cholesterol-related genes affected white matter fiber integrity; Jahanshad et al [180, 181] used the ADNI DTI and GWAS data as part of a large-scale genetic study, by the ENIGMA consortium, to discover common genetic variants that affect brain connectivity.…”

Section: Accomplishments Of the Adni Mri Core To Datementioning

confidence: 99%

Magnetic resonance imaging in Alzheimer's Disease Neuroimaging Initiative 2

Jack

Barnes

Bernstein

et al. 2015

Alzheimer's & Dementia

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INTRODUCTION ADNI is now in its 10th year. The primary objective of the MRI core of ADNI has been to improve methods for clinical trials in Alzheimer’s disease and related disorders. METHODS We review the contributions of the MRI core from present and past cycles of ADNI (ADNI 1, GO and 2). We also review plans for the future – ADNI 3. RESULTS Contributions of the MRI core include creating standardized acquisition protocols and quality control methods; examining the effect of technical features of image acquisition and analysis on outcome metrics; deriving sample size estimates for future trials based on those outcomes; and piloting the potential utility of MR perfusion, diffusion, and functional connectivity measures in multicenter clinical trials. DISCUSSION Over the past decade the MRI core of ADNI has fulfilled its mandate of improving methods for clinical trials in Alzheimer’s disease and will continue to do so in the future.

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“…12 The LDLR mediates increased astrocytic expression of APOE induced by amyloid-b, 4 whereas storage and release of cholesterol depend on the expression of the low-density lipoprotein receptor gene (LDLR), which resides within a region linked to AD in 19p13.3; rs11669576 7 and rs5930 13 are two of the most important genetic variants of the epidermal growth factor precursor homology domain of LDLR to be associated with disrupted cholesterol metabolism and variability in the risk of AD. Cholesterol governs synaptogenesis and myelin biosynthesis, 14 while the cholesteryl ester transfer protein (CETP) is associated with reverse cholesterol transport (from tissues to the liver) 5 ; protective cholesteryl ester transfer protein gene (CETP) variants lead to lower serum CETP levels and healthier lipid profiles, 15 though not all studies have shown genetically mediated lifetime cognitive effects. 16 Nevertheless, the A allele of rs708272 (TaqIB) is associated with lower serum CETP activity and lower coronary heart disease risk, 17 while the G allele of rs5882 (I422V) has been associated with lower serum CETP levels and greater white matter integrity in young adults, 14 as well as with preserved cognitive function in longevity 18 and less medial temporal lobe atrophy in APOE-e4 carriers with AD.…”

Section: Introductionmentioning

confidence: 99%

“…Cholesterol governs synaptogenesis and myelin biosynthesis, 14 while the cholesteryl ester transfer protein (CETP) is associated with reverse cholesterol transport (from tissues to the liver) 5 ; protective cholesteryl ester transfer protein gene (CETP) variants lead to lower serum CETP levels and healthier lipid profiles, 15 though not all studies have shown genetically mediated lifetime cognitive effects. 16 Nevertheless, the A allele of rs708272 (TaqIB) is associated with lower serum CETP activity and lower coronary heart disease risk, 17 while the G allele of rs5882 (I422V) has been associated with lower serum CETP levels and greater white matter integrity in young adults, 14 as well as with preserved cognitive function in longevity 18 and less medial temporal lobe atrophy in APOE-e4 carriers with AD. 19 Moreover, the nuclear liver X receptor b (LXR-b) isoform is also expressed in the brain, 4 acting as a regulator of cholesterol homeostasis, controlling amyloidogenesis, and modulating inhibition of angiotensin II, while several variants of the LXR-b gene (NR1H2) close to APOE in chromosome 19 have also been linked with variable risk of AD.…”

Section: Introductionmentioning

confidence: 99%

Associations of cerebrovascular metabolism genotypes with neuropsychiatric symptoms and age at onset of Alzheimer’s disease dementia

Oliveira

Chen

Smith

et al. 2017

Rev. Bras. Psiquiatr.

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Objective: To study associations of cerebrovascular metabolism genotypes and haplotypes with age at Alzheimer's disease dementia (AD) onset and with neuropsychiatric symptoms according to each dementia stage. Methods: Consecutive outpatients with late-onset AD were assessed for age at dementia onset and Neuropsychiatric Inventory scores according to Clinical Dementia Rating scores, apolipoprotein E gene (APOE) haplotypes, angiotensin-converting enzyme gene (ACE) variants rs1800764 and rs4291, low-density lipoprotein cholesterol receptor gene (LDLR) variants rs11669576 and rs5930, cholesteryl ester transfer protein gene (CETP) variants I422V and TaqIB, and liver X receptor beta gene (NR1H2) polymorphism rs2695121. Results: Considering 201 patients, only APOE-e4 carriers had earlier dementia onset in multiple correlations, as well as less apathy, more delusions, and more aberrant motor behavior. Both ACE polymorphisms were associated with less intense frontally mediated behaviors. Regarding LDLR variants, carriers of the A allele of rs11669576 had less anxiety and more aberrant motor behavior, whereas carriers of the A allele of rs5930 had less delusions, less anxiety, more apathy, and more irritability. CETP variants that included G alleles of I422V and TaqIB were mostly associated with less intense frontally mediated behaviors, while severely impaired carriers of the T allele of rs2695121 had more anxiety and more aberrant motor behavior. Conclusion: Though only APOE haplotypes affected AD onset, cerebrovascular metabolism genotypes were associated with differences in several neuropsychiatric manifestations of AD.

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Serum cholesterol and variant in cholesterol-related gene CETP predict white matter microstructure

Cited by 30 publications

References 85 publications

Obesity gene NEGR1 associated with white matter integrity in healthy young adults

Obesity gene NEGR1 associated with white matter integrity in healthy young adults

Magnetic resonance imaging in Alzheimer's Disease Neuroimaging Initiative 2

Associations of cerebrovascular metabolism genotypes with neuropsychiatric symptoms and age at onset of Alzheimer’s disease dementia

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