Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity

被引：115

作者：

Jahanshad, Neda ^{[1
]}

Rajagopalan, Priya ^{[1
]}

Hua, Xue ^{[1
]}

Hibar, Derrek P. ^{[1
]}

Nir, Talia M. ^{[1
]}

Toga, Arthur W. ^{[1
]}

Jack, Clifford R., Jr. ^{[2
]}

Saykin, Andrew J. ^{[3
]}

Green, Robert C. ^{[4
,5
]}

Weiner, Michael W. ^{[6
,7
]}

Medland, Sarah E. ^{[8
]}

Montgomery, Grant W. ^{[8
]}

Hansell, Narelle K. ^{[8
]}

McMahon, Katie L. ^{[9
]}

de Zubicaray, Greig I. ^{[10
]}

Martin, Nicholas G. ^{[8
]}

Wright, Margaret J. ^{[8
]}

Thompson, Paul M. ^{[1
]}

机构：

[1] Univ Calif Los Angeles, Sch Med, Lab Neuro Imaging, Imaging Genet Ctr, Los Angeles, CA 90095 USA

[2] Mayo Clin, Dept Radiol, Rochester, MN 55905 USA

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

[4] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Boston, MA 02115 USA

[6] Univ Calif San Francisco, Dept Radiol Med & Psychiat, San Francisco, CA 94121 USA

[7] Dept Vet Affairs Med Ctr, Magnet Resonance Spect Unit, San Francisco, CA 94121 USA

[8] Queensland Inst Med Res, Dept Genet, Brisbane, Qld 4029, Australia

[9] Univ Queensland, Ctr Adv Imaging, Brisbane, Qld 4072, Australia

[10] Univ Queensland, Sch Psychol, Brisbane, Qld 4072, Australia

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2013年 / 110卷 / 12期

基金：

澳大利亚国家健康与医学研究理事会; 英国医学研究理事会; 美国国家科学基金会; 美国国家卫生研究院; 澳大利亚研究理事会;

关键词：

diffusion tensor imaging; neuroimaging genetics; graph theory; HARDI tractography; multiple comparisons correction; AMYLOID PRECURSOR PROTEIN; ALZHEIMERS-DISEASE; F-SPONDIN; COMMON VARIANTS; BETA; ORGANIZATION; NETWORKS; MATTER; RISK; HIPPOCAMPAL;

D O I：

10.1073/pnas.1216206110

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer's disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, high-angular resolution diffusion MRI. We adapted GWASs to screen the brain's connectivity pattern, allowing us to discover genetic variants that affect the human brain's wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer's disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism (MACROD2), development (NEDD4), and mental retardation (UBE2A) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases.

引用

页码：4768 / 4773

页数：6

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