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

Research output: Contribution to journalArticle

87 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 languageEnglish (US)
Pages (from-to)4768-4773
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number12
DOIs
StatePublished - Mar 19 2013

    Fingerprint

Keywords

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

ASJC Scopus subject areas

  • General

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