Raffield Laura M, Cox Amanda J, Hugenschmidt Christina E, Freedman Barry I, Langefeld Carl D, Williamson Jeff D, Hsu Fang-Chi, Maldjian Joseph A, Bowden Donald W
Molecular Genetics and Genomics Program, Wake Forest School of Medicine, Winston-Salem, NC, USA; Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA; Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA; Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA; Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Neurobiol Aging. 2015 Mar;36(3):1602.e7-15. doi: 10.1016/j.neurobiolaging.2014.11.008. Epub 2014 Nov 20.
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 (ĥ(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.
2型糖尿病患者发生与年龄相关的认知功能减退和痴呆的风险增加。诸如白质病变体积、脑容量和分数各向异性等神经影像学指标可能反映了这些认知功能减退的发病机制，而遗传因素可能导致这些指标的变异性。本研究在238个家庭的465名参与者中检测了多种神经影像学指标，这些家庭在富含2型糖尿病的糖尿病心脏研究-心智队列中有广泛的基因型数据。探讨了这些表型的遗传力及其与候选单核苷酸多态性（SNP）的关联，以及来自全基因组和外显子组阵列的SNP数据。所有分析的神经影像学指标均具有显著遗传性（未校正模型中ĥ(2)=0.55-0.99）。先前研究中与神经影像学表型相关的17个候选SNP（来自16个基因/区域）未显示出显著的关联证据。外显子组阵列中PLEKHG4B的一个错义变异（rs150706952，A432V）与白质平均扩散率（p=3.66×10^(-7)）和灰质平均扩散率（p=2.14×10^(-7)）显著相关。该分析表明，遗传因素在富含代谢疾病和其他相关合并症的人群中导致神经影像学指标的变异。
