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Do Candidate Genes Affect the Brain's White Matter Microstructure? Large-Scale Evaluation of 6,165 Diffusion MRI Scans
By
Neda Jahanshad,
Habib Ganjgahi,
Janita Bralten,
Anouk den Braber,
Joshua Faskowitz,
Annchen Knodt,
Herve Lemaitre,
Talia Nir,
Binish Patel,
Stuart Richie,
Emma Sprooten,
Kimm van Hulzen,
Artemis Zavaliangos-Petropulu,
Marcel Zwiers,
Laura Almasy,
Mark Bastin,
Matt Bernstein,
John Blangero,
Joanne Curran,
Ian J Deary,
Greig de Zubicary,
Ravi Duggirala,
Simon Fisher,
Barbara Franke,
Peter Fox,
David Goldman,
Asta Haberg,
Ahmad Hariri,
L Elliot Hong,
Martine Hoogman,
Matt Huentelman,
Nicholas Martin,
Jean-Luc Martinot,
Andrew McIntosh,
Katie McMahon,
Sarah Medland,
Braxton Mitchell,
Susana Muñoz-Maniega,
Rene Olvera,
Jaap Oosterlaan,
Charles Peterson,
Natalie Royle,
Andrew Saykin,
Gunter Schumann,
John Starr,
Elliot A Stein,
Jessika Sussmann,
Maria Valdez-Hernan,
Dennis van't Ent,
Joanna Wardlaw,
Michael Weiner,
Douglas E Williamson,
Anderson Winkler,
Margaret J Wright,
Yihong Yang,
Paul M Thompson,
David C Glahn,
Thomas E Nichols,
Peter Kochunov
Posted 20 Feb 2017
bioRxiv DOI: 10.1101/107987
Susceptibility genes for psychiatric and neurological disorders - including APOE, BDNF, CLU, CNTNAP2, COMT, DISC1, DTNBP1, ErbB4, HFE, NRG1, NTKR3, and ZNF804A - have been reported to affect white matter (WM) microstructure in the healthy human brain, as assessed through diffusion tensor imaging (DTI). However, effects of single nucleotide polymorphisms (SNPs) in these genes explain only a small fraction of the overall variance and are challenging to detect reliably in single cohort studies. To date, few studies have evaluated the reproducibility of these results. As part of the ENIGMA-DTI consortium, we pooled regional fractional anisotropy (FA) measures for 6,165 subjects (CEU ancestry N=4,458) from 11 cohorts worldwide to evaluate effects of 15 candidate SNPs by examining their associations with WM microstructure. Additive association tests were conducted for each SNP. We used several meta-analytic and mega-analytic designs, and we evaluated regions of interest at multiple granularity levels. The ENIGMA-DTI protocol was able to detect single-cohort findings as originally reported. Even so, in this very large sample, no significant associations remained after multiple-testing correction for the 15 SNPs investigated. Suggestive associations (1.3x10-4 < p < 0.05, uncorrected) were found for BDNF, COMT, and ZNF804A in specific tracts. Meta- and mega-analyses revealed similar findings. Regardless of the approach, the previously reported candidate SNPs did not show significant associations with WM microstructure in this largest genetic study of DTI to date; the negative findings are likely not due to insufficient power. Genome-wide studies, involving large-scale meta-analyses, may help to discover SNPs robustly influencing WM microstructure.
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