title: A genome-wide search for genetic influences and biological pathways related to the brain's white matter integrity.
abstract: A genome-wide search for genetic variants influencing the brain's white matter integrity in old age was conducted in the Lothian Birth Cohort 1936 (LBC1936). At ∼73 years of age, members of the LBC1936 underwent diffusion MRI, from which 12 white matter tracts were segmented using quantitative tractography, and tract-averaged water diffusion parameters were determined (n = 668). A global measure of white matter tract integrity, g(FA), derived from principal components analysis of tract-averaged fractional anisotropy measurements, accounted for 38.6% of the individual differences across the 12 white matter tracts. A genome-wide search was performed with g(FA) on 535 individuals with 542,050 single nucleotide polymorphisms (SNPs). No single SNP association was genome-wide significant (all p > 5 × 10(-8)). There was genome-wide suggestive evidence for two SNPs, one in ADAMTS18 (p = 1.65 × 10(-6)), which is related to tumor suppression and hemostasis, and another in LOC388630 (p = 5.08 × 10(-6)), which is of unknown function. Although no gene passed correction for multiple comparisons in single gene-based testing, biological pathways analysis suggested evidence for an over-representation of neuronal transmission and cell adhesion pathways relating to g(FA).
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, The University of Edinburgh, Edinburgh, UK. lorna.lopez@ed.ac.uk
authors.forename: Lorna M
authors.initials: LM
authors.lastname: Lopez
authors.forename: Mark E
authors.initials: ME
authors.lastname: Bastin
authors.forename: Susana Muñoz
authors.initials: SM
authors.lastname: Maniega
authors.forename: Lars
authors.initials: L
authors.lastname: Penke
authors.forename: Gail
authors.initials: G
authors.lastname: Davies
authors.forename: Andrea
authors.initials: A
authors.lastname: Christoforou
authors.forename: Maria C
authors.initials: MC
authors.lastname: Valdés Hernández
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Royle
authors.forename: Albert
authors.initials: A
authors.lastname: Tenesa
authors.forename: John M
authors.initials: JM
authors.lastname: Starr
authors.forename: David J
authors.initials: DJ
authors.lastname: Porteous
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Wardlaw
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Deary
mesh_terms: D000368:Aged; D000375:Aging / Q000473:pathology* / Q000502:physiology*; D005260:Female; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D008297:Male; D009413:Nerve Fibers, Myelinated / Q000502:physiology* / Q000648:ultrastructure*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D009419:Nerve Tissue Proteins