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

Neda Jahanshad; Priya Rajagopalan; Xue Hua; Derrek P. Hibar; Talia M. Nir; Arthur W. Toga; Clifford R. Jack; Andrew J. Saykin; Robert C. Green; Michael W. Weiner; Sarah E. Medland; Grant W. Montgomery; Narelle K. Hansell; Katie L. McMahon; Greig I. De Zubicaray; Nicholas G. Martin; Margaret J. Wright; Paul M. Thompson

doi:10.1073/pnas.1216206110

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

Neda Jahanshad, Priya Rajagopalan, Xue Hua, Derrek P. Hibar, Talia M. Nir, Arthur W. Toga, Clifford R. Jack, Andrew J. Saykin, Robert C. Green, Michael W. Weiner, Sarah E. Medland, Grant W. Montgomery, Narelle K. Hansell, Katie L. McMahon, Greig I. De Zubicaray, Nicholas G. Martin, Margaret J. Wright, Paul M. Thompson

Radiology

Research output: Contribution to journal › Article › peer-review

104 Scopus citations

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.

Original language	English (US)
Pages (from-to)	4768-4773
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	110
Issue number	12
DOIs	https://doi.org/10.1073/pnas.1216206110
State	Published - Mar 19 2013

Keywords

Diffusion tensor imaging
Graph theory
HARDI tractography
Multiple comparisons correction
Neuroimaging genetics

ASJC Scopus subject areas

General

Access to Document

10.1073/pnas.1216206110

Cite this

Jahanshad, N., Rajagopalan, P., Hua, X., Hibar, D. P., Nir, T. M., Toga, A. W., Jack, C. R., Saykin, A. J., Green, R. C., Weiner, M. W., Medland, S. E., Montgomery, G. W., Hansell, N. K., McMahon, K. L., De Zubicaray, G. I., Martin, N. G., Wright, M. J., & Thompson, P. M. (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. https://doi.org/10.1073/pnas.1216206110

Jahanshad, N, Rajagopalan, P, Hua, X, Hibar, DP, Nir, TM, Toga, AW, Jack, CR, Saykin, AJ, Green, RC, Weiner, MW, Medland, SE, Montgomery, GW, Hansell, NK, McMahon, KL, De Zubicaray, GI, Martin, NG, Wright, MJ & Thompson, PM 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, vol. 110, no. 12, pp. 4768-4773. https://doi.org/10.1073/pnas.1216206110

@article{e10242b097f5434fb839b0f626debb7d,

title = "Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity",

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.",

keywords = "Diffusion tensor imaging, Graph theory, HARDI tractography, Multiple comparisons correction, Neuroimaging genetics",

author = "Neda Jahanshad and Priya Rajagopalan and Xue Hua and Hibar, {Derrek P.} and Nir, {Talia M.} and Toga, {Arthur W.} and Jack, {Clifford R.} and Saykin, {Andrew J.} and Green, {Robert C.} and Weiner, {Michael W.} and Medland, {Sarah E.} and Montgomery, {Grant W.} and Hansell, {Narelle K.} and McMahon, {Katie L.} and {De Zubicaray}, {Greig I.} and Martin, {Nicholas G.} and Wright, {Margaret J.} and Thompson, {Paul M.}",

year = "2013",

month = mar,

day = "19",

doi = "10.1073/pnas.1216206110",

language = "English (US)",

volume = "110",

pages = "4768--4773",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "12",

}

TY - JOUR

T1 - Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity

AU - Jahanshad, Neda

AU - Rajagopalan, Priya

AU - Hua, Xue

AU - Hibar, Derrek P.

AU - Nir, Talia M.

AU - Toga, Arthur W.

AU - Jack, Clifford R.

AU - Saykin, Andrew J.

AU - Green, Robert C.

AU - Weiner, Michael W.

AU - Medland, Sarah E.

AU - Montgomery, Grant W.

AU - Hansell, Narelle K.

AU - McMahon, Katie L.

AU - De Zubicaray, Greig I.

AU - Martin, Nicholas G.

AU - Wright, Margaret J.

AU - Thompson, Paul M.

PY - 2013/3/19

Y1 - 2013/3/19

N2 - 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.

AB - 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.

KW - Diffusion tensor imaging

KW - Graph theory

KW - HARDI tractography

KW - Multiple comparisons correction

KW - Neuroimaging genetics

UR - http://www.scopus.com/inward/record.url?scp=84875269684&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875269684&partnerID=8YFLogxK

U2 - 10.1073/pnas.1216206110

DO - 10.1073/pnas.1216206110

M3 - Article

C2 - 23471985

AN - SCOPUS:84875269684

SN - 0027-8424

VL - 110

SP - 4768

EP - 4773

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 12

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this