Whole genome association study of brain-wide imaging phenotypes for identifying quantitative trait loci in MCI and AD: A study of the ADNI cohort

被引：278

作者：

Shen, Li ^{[1
,2
]}

Kim, Sungeun ^{[1
,2
]}

Risacher, Shannon L. ^{[1
]}

Nho, Kwangsik ^{[1
,3
]}

Swaminathan, Shanker ^{[1
,4
]}

West, John D. ^{[1
]}

Foroud, Tatiana ^{[4
]}

Pankratz, Nathan ^{[4
]}

Moore, Jason H. ^{[5
,6
]}

Sloan, Chantel D. ^{[5
,6
]}

Huentelman, Matthew J. ^{[7
]}

Craig, David W. ^{[7
]}

DeChairo, Bryan M. ^{[8
]}

Potkin, Steven G. ^{[9
]}

Jack, Clifford R., Jr. ^{[10
]}

Weiner, Michael W. ^{[11
,12
,13
]}

Saykin, Andrew J. ^{[1
,4
]}

机构：

[1] Indiana Univ Sch Med, Dept Radiol & Imaging Sci, Ctr Neuroimaging, Indianapolis, IN 46202 USA

[2] Indiana Univ Sch Med, Ctr Computat Biol & Bioinformat, Indianapolis, IN 46202 USA

[3] Regenstrief Inst Hlth Care, Indianapolis, IN 46202 USA

[4] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA

[5] Dartmouth Med Sch, Computat Genet Lab, Dept Genet, Lebanon, NH 03756 USA

[6] Dartmouth Med Sch, Computat Genet Lab, Dept Community & Family Med, Lebanon, NH 03756 USA

[7] Translat Genom Res Inst, Phoenix, AZ 85004 USA

[8] Pfizer Global R&D, Mol Med, Neurosci, New London, CT 06320 USA

[9] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92697 USA

[10] Mayo Clin, Rochester, MN 55905 USA

[11] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA

[12] Univ Calif San Francisco, Dept Med & Psychiat, San Francisco, CA 94143 USA

[13] Dept Vet Affairs Med Ctr, San Francisco, CA 94121 USA

来源：

NEUROIMAGE | 2010年 / 53卷 / 03期

关键词：

SURFACE-BASED ANALYSIS; GENETIC ASSOCIATIONS; ALZHEIMER-DISEASE; CANDIDATE GENE; MRI; EPSILON-4; ATROPHY; SUSCEPTIBILITY; SEGMENTATION; EXPRESSION;

D O I：

10.1016/j.neuroimage.2010.01.042

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

A genome-wide, whole brain approach to investigate genetic effects on neuroimaging phenotypes for identifying quantitative trait loci is described. The Alzheimer's Disease Neuroimaging Initiative 1.5 T MRI and genetic dataset was investigated using voxel-based morphometry (VBM) and FreeSurfer parcellation followed by genome-wide association studies (GWAS). One hundred forty-two measures of grey matter (GM) density, volume, and cortical thickness were extracted from baseline scans. GWAS, using PLINK, were performed on each phenotype using quality-controlled genotype and scan data including 530,992 of 620,903 single nucleotide polymorphisms (SNPs) and 733 of 818 participants (175 AD, 354 amnestic mild cognitive impairment, MCI, and 204 healthy controls, HC). Hierarchical clustering and heat maps were used to analyze the GWAS results and associations are reported at two significance thresholds (p<10(-7) and p<10(-6)). As expected, SNPs in the APOE and TOMM40 genes were confirmed as markers strongly associated with multiple brain regions. Other top SNPs were proximal to the EPHA4, TP63 and NXPH1 genes. Detailed image analyses of rs6463843 (flanking NXPH1) revealed reduced global and regional GM density across diagnostic groups in TT relative to GG homozygotes. Interaction analysis indicated that AD patients homozygous for the T allele showed differential vulnerability to right hippocampal GM density loss. NXPH1 codes for a protein implicated in promotion of adhesion between dendrites and axons, a key factor in synaptic integrity, the loss of which is a hallmark of AD. A genome-wide, whole brain search strategy has the potential to reveal novel candidate genes and loci warranting further investigation and replication. (c) 2010 Elsevier Inc. All rights reserved.

引用

页码：1051 / 1063

页数：13

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