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

Jahanshad, Neda, Rajagopalan, Priya, Hua, Xue, Hibar, Derrek P., Nir, Talia M., Toga, Arthur W., Jack, Jr, Clifford R., Saykin, Andrew J., Green, Robert C., Weiner, Michael W., Medland, Sarah E., Montgomery, Grant W., Hansell, Narelle K., McMahon, Katie L., de Zubicaray, Greig I., Martin, Nicholas G., Wright, Margaret J., Thompson, Paul M. and The Alzheimer’s Disease Neuroimaging Initiative (2013) Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity. Proceedings of the National Academy of Sciences of the United States of America, 110 12: 4768-4773. doi:10.1073/pnas.1216206110

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Author Jahanshad, Neda
Rajagopalan, Priya
Hua, Xue
Hibar, Derrek P.
Nir, Talia M.
Toga, Arthur W.
Jack, Jr, Clifford R.
Saykin, Andrew J.
Green, Robert C.
Weiner, Michael W.
Medland, Sarah E.
Montgomery, Grant W.
Hansell, Narelle K.
McMahon, Katie L.
de Zubicaray, Greig I.
Martin, Nicholas G.
Wright, Margaret J.
Thompson, Paul M.
The Alzheimer’s Disease Neuroimaging Initiative
Title Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity
Formatted title
Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity
Journal name Proceedings of the National Academy of Sciences of the United States of America   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2013-03-19
Year available 2013
Sub-type Article (original research)
DOI 10.1073/pnas.1216206110
Open Access Status Not yet assessed
Volume 110
Issue 12
Start page 4768
End page 4773
Total pages 6
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Language eng
Subject 1000 General
Abstract 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, highangular 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.
Keyword Diffusion tensor imaging
Graph theory
HARDI tractography
Multiple comparisons correction
Neuroimaging genetics
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID MC_U137761446
Institutional Status UQ

 
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Created: Wed, 20 Mar 2013, 20:20:11 EST by Sandrine Ducrot on behalf of Centre for Advanced Imaging