Maryland Psychiatric Research Center, University of Maryland School of Medicine Baltimore, MD, USA.
Front Neurosci. 2011 Oct 19;5:120. doi: 10.3389/fnins.2011.00120. eCollection 2011.
The thickness of the brain's cortical gray matter (GM) and the fractional anisotropy (FA) of the cerebral white matter (WM) each follow an inverted U-shape trajectory with age. The two measures are positively correlated and may be modulated by common biological mechanisms. We employed four types of genetic analyses to localize individual genes acting pleiotropically upon these phenotypes.
Whole-brain and regional GM thickness and FA values were measured from high-resolution anatomical and diffusion tensor MR images collected from 712, Mexican American participants (438 females, age = 47.9 ± 13.2 years) recruited from 73 (9.7 ± 9.3 individuals/family) large families. The significance of the correlation between two traits was estimated using a bivariate genetic correlation analysis. Localization of chromosomal regions that jointly influenced both traits was performed using whole-genome quantitative trait loci (QTL) analysis. Gene localization was performed using SNP genotyping on Illumina 1M chip and correlation with leukocyte-based gene-expression analyses. The gene-expressions were measured using the Illumina BeadChip. These data were available for 371 subjects.
Significant genetic correlation was observed among GM thickness and FA values. Significant logarithm of odds (LOD ≥ 3.0) QTLs were localized within chromosome 15q22-23. More detailed localization reported no significant association (p < 5·10(-5)) for 1565 SNPs located within the QTLs. Post hoc analysis indicated that 40% of the potentially significant (p ≤ 10(-3)) SNPs were localized to the related orphan receptor alpha (RORA) and NARG2 genes. A potentially significant association was observed for the rs2456930 polymorphism reported as a significant GWAS finding in Alzheimer's disease neuroimaging initiative subjects. The expression levels for RORA and ADAM10 genes were significantly (p < 0.05) correlated with both FA and GM thickness. NARG2 expressions were significantly correlated with GM thickness (p < 0.05) but failed to show a significant correlation (p = 0.09) with FA.
This study identified a novel, significant QTL at 15q22-23. SNP correlation with gene-expression analyses indicated that RORA, NARG2, and ADAM10 jointly influence GM thickness and WM-FA values.
大脑皮质灰质（GM）的厚度和脑白质（WM）的各向异性分数（FA）都随年龄呈倒 U 型轨迹变化。这两个指标呈正相关，可能受到共同的生物学机制的调节。我们采用了四种类型的遗传分析方法，来定位对这些表型具有多效性作用的个体基因。
从 712 名墨西哥裔美国参与者（438 名女性，年龄=47.9±13.2 岁）的高分辨率解剖和扩散张量磁共振图像中测量了全脑和区域 GM 厚度和 FA 值，这些参与者是从 73 个（9.7±9.3 人/家）大家庭中招募而来的。使用双变量遗传相关分析来估计两个特征之间相关性的显著性。使用全基因组数量性状基因座（QTL）分析来定位共同影响两个特征的染色体区域。使用 Illumina 1M 芯片进行 SNP 基因分型，并与基于白细胞的基因表达分析进行相关性分析。这些数据可用于 371 名受试者。
GM 厚度和 FA 值之间观察到显著的遗传相关性。在染色体 15q22-23 内定位到显著的对数优势（LOD≥3.0）QTL。在 QTL 内定位到的 1565 个 SNP 进行更详细的定位，没有发现显著的关联（p<5·10(-5)）。事后分析表明，在与阿尔茨海默病神经影像学倡议（Alzheimer's disease neuroimaging initiative）受试者的全基因组关联研究（GWAS）结果相关的 40%的潜在显著（p≤10(-3)）SNP 被定位到相关的孤儿受体α（RORA）和 NARG2 基因上。在 ADAM10 基因中，rs2456930 多态性与 FA 和 GM 厚度呈显著正相关（p<0.05）。NARG2 表达与 GM 厚度呈显著正相关（p<0.05），但与 FA 无显著相关性（p=0.09）。
本研究在 15q22-23 发现了一个新的、显著的 QTL。SNP 与基因表达分析的相关性表明，RORA、NARG2 和 ADAM10 共同影响 GM 厚度和 WM-FA 值。
