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Heritability and genetic association analysis of neuroimaging measures in the Diabetes Heart Study.

ABSTRACT: Patients with type 2 diabetes are at increased risk of age-related cognitive decline and dementia. Neuroimaging measures such as white matter lesion volume, brain volume, and fractional anisotropy may reflect the pathogenesis of these cognitive declines, and genetic factors may contribute to variability in these measures. This study examined multiple neuroimaging measures in 465 participants from 238 families with extensive genotype data in the type 2 diabetes enriched Diabetes Heart Study-Mind cohort. Heritability of these phenotypes and their association with candidate single-nucleotide polymorphisms (SNPs), and SNP data from genome- and exome-wide arrays were explored. All neuroimaging measures analyzed were significantly heritable (?(2) = 0.55-0.99 in unadjusted models). Seventeen candidate SNPs (from 16 genes/regions) associated with neuroimaging phenotypes in prior studies showed no significant evidence of association. A missense variant (rs150706952, A432V) in PLEKHG4B from the exome-wide array was significantly associated with white matter mean diffusivity (p = 3.66 × 10(-7)) and gray matter mean diffusivity (p = 2.14 × 10(-7)). This analysis suggests genetic factors contribute to variation in neuroimaging measures in a population enriched for metabolic disease and other associated comorbidities.

SUBMITTER: Raffield LM

PROVIDER: S-EPMC4346514 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Heritability and genetic association analysis of neuroimaging measures in the Diabetes Heart Study.

Raffield Laura M LM Cox Amanda J AJ Hugenschmidt Christina E CE Freedman Barry I BI Langefeld Carl D CD Williamson Jeff D JD Hsu Fang-Chi FC Maldjian Joseph A JA Bowden Donald W DW

Neurobiology of aging 20141120 3

Patients with type 2 diabetes are at increased risk of age-related cognitive decline and dementia. Neuroimaging measures such as white matter lesion volume, brain volume, and fractional anisotropy may reflect the pathogenesis of these cognitive declines, and genetic factors may contribute to variability in these measures. This study examined multiple neuroimaging measures in 465 participants from 238 families with extensive genotype data in the type 2 diabetes enriched Diabetes Heart Study-Mind ...[more]

PMID: 25523635

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Project description:Ectopic fat accumulation in the renal sinus is associated with chronic kidney disease and hypertension. The genetic contributions to renal sinus fat accumulation in humans have not been well characterized.The present analysis consists of participants from the Framingham Offspring and Third Generation who underwent computed tomography; renal sinus fat and visceral adipose tissue (VAT) were quantified. Renal sinus fat was natural log transformed and sex- and cohort-specific residuals were created, adjusted for (1) age, (2) age and body mass index (BMI), and (3) age and VAT. Residuals were pooled and used to calculate heritability using variance-components analysis in SOLAR. A genome-wide association study (GWAS) for renal sinus fat was performed using an additive model with approximately 2.5 million imputed single nucleotide polymorphisms (SNPs). Finally, we identified the associations of renal sinus fat in our GWAS results with validated SNPs for renal function (n=16), BMI (n=32), and waist-to-hip ratio (WHR, n=14), and applied a multi-SNP genetic risk score method to determine if the SNPs for each renal and obesity trait were in aggregate associated with renal sinus fat.The heritability of renal sinus fat was 39% (p<0.0001); results were not materially different after adjustment for BMI (39%) or VAT (40%). No SNPs reached genome-wide significance in our GWAS. In our candidate gene analysis, we observed nominal, direction consistent associations with renal sinus fat for one SNP associated with renal function (p=0.01), two associated with BMI (p<0.03), and two associated with WHR (p<0.03); however, none remained significant after accounting for multiple testing. Finally, we observed that in aggregate, the 32 SNPs associated with BMI were nominally associated with renal sinus fat (multi-SNP genetic risk score p=0.03).Renal sinus fat is a heritable trait, even after accounting for generalized and abdominal adiposity. This provides support for further research into the genetic determinants of renal sinus fat. While our study was underpowered to detect genome-wide significant loci, our candidate gene BMI risk score results suggest that variability in renal sinus fat may be associated with SNPs previously known to be associated with generalized adiposity.

Dataset Information

Heritability and genetic association analysis of neuroimaging measures in the Diabetes Heart Study.

Publications

Heritability and genetic association analysis of neuroimaging measures in the Diabetes Heart Study.

Similar Datasets

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