TY - JOUR T1 - Do Candidate Genes Affect the Brain’s White Matter Microstructure? Large-Scale Evaluation of 6,165 Diffusion MRI Scans JF - bioRxiv DO - 10.1101/107987 SP - 107987 AU - Neda Jahanshad, PhD AU - Habib Ganjgahi, MS AU - Janita Bralten, PhD AU - Anouk den Braber, PhD AU - Joshua Faskowitz, BS AU - Annchen R Knodt, MS AU - Hervé Lemaitre, PhD AU - Talia M Nir, BS AU - Binish Patel, BS AU - Stuart Richie, PhD AU - Emma Sprooten, PhD AU - Martine Hoogman, PhD AU - Kimm van Hulzen, PhD AU - Artemis Zavaliangos-Petropulu, BS AU - Marcel P Zwiers, PhD AU - Laura Almasy, PhD AU - Mark E Bastin, PhD AU - Matt A Bernstein, PhD AU - John Blangero, PhD AU - Joanne Curran, PhD AU - Ian J Deary, PhD AU - Greig I de Zubicary, PhD AU - Ravi Duggirala, PhD AU - Simon E Fisher, DPhil AU - Barbara Franke, PhD AU - Peter Fox MD AU - David Goldman, PhD AU - Asta K Haberg, PhD AU - Ahmad Hariri, PhD AU - L Elliot Hong MD AU - Matt Huentelman, PhD AU - Nicholas G Martin, PhD AU - Jean-Luc Martinot, PhD AU - Andrew McIntosh, PhD AU - Katie L McMahon, PhD AU - Sarah E Medland, PhD AU - Braxton D Mitchell, PhD AU - Susana Muñoz Maniega, PhD AU - Rene L Olvera, PhD AU - Jaap Oosterlaan, PhD AU - Charles Peterson, PhD AU - Natalie Royle, PhD AU - Andrew J Saykin, PsyD AU - Gunter Schumann, PhD AU - John Starr, PhD AU - Elliot A Stein, PhD AU - Jessika Sussmann, PhD AU - Maria del C. Valdés Hernández, PhD AU - Dennis van’t Ent, PhD AU - Joanna M Wardlaw MD AU - Michael W Weiner MD AU - Douglas E Williamson, PhD AU - Anderson M Winkler MD AU - Margaret J Wright, PhD AU - Yihong Yang, PhD AU - Paul M Thompson, PhD AU - David C Glahn, PhD AU - Thomas E Nichols, PhD AU - Peter Kochunov, PhD Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/02/20/107987.abstract N2 - 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 (1.3×10-4 < 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. ER -