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Multi-Site Genetic Analysis of 1151 Diffusion MRI Scans from the ENIGMA–DTI Working Group

Multi-Site Genetic Analysis of 1151 Diffusion MRI Scans from the ENIGMA–DTI Working Group.

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Multi-Site Genetic Analysis of 1151 Diffusion MRI Scans from the ENIGMA–DTI Working Group

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  1. Multi-Site Genetic Analysis of 1151 Diffusion MRI Scansfromthe ENIGMA–DTI Working Group Neda Jahanshad1#, Peter Kochunov2#, Emma Sprooten3,4, René C. Mandl5, Thomas E. Nichols6,7, Laura Almasy8, John Blangero8, Rachel M. Brouwer4, Joanne E. Curran8, Greig I. de Zubicaray9, Ravi Duggirala8, Peter T. Fox10, L. Elliot Hong2, Bennett A. Landman11, Nicholas G. Martin12, Katie L. McMahon13, Sarah E. Medland12, Braxton D. Mitchell14, Rene L. Olvera10, Charles P. Peterson8, John M. Starr15, Jessika E. Sussmann4, Arthur W. Toga1, Joanna M. Wardlaw15, Margaret J. Wright12, Hilleke E. Hulshoff Pol5, Mark E. Bastin4,15, Andrew M. McIntosh4, Ian J. Deary15, Paul M. Thompson1*and David C. Glahn3 Neda.Jahanshad@loni.ucla.edu Joint work with UCLA, U. MD, U. Edinburgh, UMC Utrecht, U. Warwick, Vanderbilt, U. TX San Antonio, U. Queensland, QTIM, Yale

  2. Meta analysis for genetic studies • A search for “meta-analysis” revealed 400+ articles in Nature Genetics in the last 10 years! • ~20%!! • What is meta-analysis? • Genetics - MA  Importantdiscoveries for: • AD/neurodegeneration • Psychiatric disorders • Behavior and cognition

  3. Meta analysis for genetic studies Imaging 26,000+ Images! Stein et al., 2012 Bis et al., 2012, Ikram et al., 2012, Taal et al, 2012

  4. Genome-wide association study (GWAS)with imaging phenotypes (ICV) Genome-wide significance threshold Image courtesy of Dr. Jason Stein (that guy)

  5. White Matter - Heritability, Risk GenesDTI

  6. GWAS using DTI phenotypes • Single site studies of white matter integrity • Global measure of FA • General factor of FA • Top SNPs in candidate pathways • No “genome-wide” significant findings • Relatively small sample sizes • N~150, N~700

  7. Multi-site DTI • Greatly increase the number of subjects • Genome wide significance? • Would a tract from one study be the same as a tract from another? • How reliable are the tracts in terms of imaging protocol and resolution • DTI reliability studies • Magnotta et al., 2012 • Jahanshad et al., 2010,2012 • Zhan et al., 2012 • Walker et al., 2012 • Teipel et al., 2011 • Planning studies, not mergingexistingdata

  8. Combining DTI - Initial Steps • Create common template • Widely used tract based spatial statistics skeletonization • (Smith et al., 2006) FSL -- http://fsl.fmrib.ox.ac.uk/fsl/

  9. BFS • Scanner: GE • Field Strength: 1.5T • Voxel size (mm): 2.5x2.5x2.5 • N-gradients: 64 • QTIM • Scanner: Bruker • Field Strength: 4T • Voxel size (mm): 1.8x1.8x2 • N-gradients: 94 • LBC1936 • Scanner: GE • Field Strength: 1.5T • Voxel size (mm): 2.0x2.0x2.0 • N-gradients: 64 • GOBS • Scanner: Siemens • Field Strength: 3T • Voxel size (mm): 1.7x1.7x3 • N-gradients: 55 • UMCU • Scanner: Achieva • Field Strength: 1.5T • Voxel size (mm): 2.5x2.5x2.5 • N-gradients: 32

  10. Multi-site DTI GWAS • Would tracts from different populations or datasets even be similarly heritable? • Blokland et al., 2012 • Could they be used as endophenotypes for GWAS regardless of protocol?

  11. Let’s find out! • Multi-site heritability analysis C A C E E A • QTIM • 292 Australian twins of European ancestry (146 pairs) • 68 monozygotic (MZ) pairs, and 78 dizygotic (DZ) • 106 male/ 186 female • mean age 23.0 (SD = 2.0 ; range = 21-29). • GOBS • 859 Mexican-American individuals from 73 extended pedigrees (average size 17.2 people, range = 1-247) • 351 men/508 women • mean age of 43.2 (SD = 15.0; range = 19-85). c c a e e a Twin1 Twin2

  12. ROI heritability results

  13. Meta-analysis of heritability

  14. Meta-analysis of heritability

  15. Mega-analysis of heritability N=1151 SequentialOligogenicLinkage Analysis Routines

  16. Single Site GWAS Q-Q plots

  17. Preprocessing • Initial quality control • Creating FA maps • Registration to template and skeletonization • Intermediate QC • Projection distance • ROI extraction • Final quality control • Visual inspection of images • Histograms and outlier detection • GWAS / Other analysis

  18. AcknowledgementsENIGMA DTI sites JOIN US  Peter Kochunov2#, Emma Sprooten3,4, René C. Mandl5, Thomas E. Nichols6,7, Laura Almasy8, John Blangero8, Rachel M. Brouwer4, Joanne E. Curran8, Greig I. de Zubicaray9, Ravi Duggirala8, Peter T. Fox10, L. Elliot Hong2, Bennett A. Landman11, Nicholas G. Martin12, Katie L. McMahon13, Sarah E. Medland12, Braxton D. Mitchell14, Rene L. Olvera10, Charles P. Peterson8, John M. Starr15, Jessika E. Sussmann4, Arthur W. Toga1, Joanna M. Wardlaw15, Margaret J. Wright12, Hilleke E. Hulshoff Pol5, Mark E. Bastin4,15, Andrew M. McIntosh4, Ian J. Deary15, Paul M. Thompson1*and David C. Glahn3 Join ENIGMA http://enigma.loni.ucla.edu/members/join/ Neda.Jahanshad@loni.ucla.edu US/Australia/European funding agencies

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