1. Multi-Site Genetic Analysis of 1151 Diffusion MRI Scans from the ENIGMA–DTI Working Group Neda Jahanshad 1#, Peter Kochunov 2#, Emma Sprooten 3,4, René C. Mandl 5, Thomas E. Nichols 6,7, Laura Almasy 8, John Blangero 8, Rachel M. Brouwer 4, Joanne E. Curran 8, Greig I. de Zubicaray 9, Ravi Duggirala 8, Peter T. Fox 10, L. Elliot Hong 2, Bennett A. Landman 11, Nicholas G. Martin 12, Katie L. McMahon 13, Sarah E. Medland 12, Braxton D. Mitchell 14, Rene L. Olvera 10, Charles P. Peterson 8, John M. Starr 15, Jessika E. Sussmann 4, Arthur W. Toga 1, Joanna M. Wardlaw 15, Margaret J. Wright 12, Hilleke E. Hulshoff Pol 5, Mark E. Bastin 4,15, Andrew M. McIntosh 4, Ian J. Deary 15, Paul M. Thompson 1* and David C. Glahn 3 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  Important discoveries for: – AD/neurodegeneration – Psychiatric disorders – Behavior and cognition

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

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 Genes DTI

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 merging existing data

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/http://fsl.fmrib.ox.ac.uk/fsl/

9. 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 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 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 E CA A CE Twin1 Twin2 e c a a c e 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).

12. ROI heritability results

13. Meta-analysis of heritability

15. Mega-analysis of heritability N=1151

16. Single Site GWAS Q-Q plots

17. 1.Preprocessing – Initial quality control – Creating FA maps 2.Registration to template and skeletonization – Intermediate QC – Projection distance 3.ROI extraction 4.Final quality control – Visual inspection of images – Histograms and outlier detection 5.GWAS / Other analysis

18. Acknowledgements ENIGMA DTI sites Join ENIGMA http://enigma.loni.ucla.edu/members/join/ Neda.Jahanshad@loni.ucla.edu US/Australia/European funding agencies Peter Kochunov 2#, Emma Sprooten 3,4, René C. Mandl 5, Thomas E. Nichols 6,7, Laura Almasy 8, John Blangero 8, Rachel M. Brouwer 4, Joanne E. Curran 8, Greig I. de Zubicaray 9, Ravi Duggirala 8, Peter T. Fox 10, L. Elliot Hong 2, Bennett A. Landman 11, Nicholas G. Martin 12, Katie L. McMahon 13, Sarah E. Medland 12, Braxton D. Mitchell 14, Rene L. Olvera 10, Charles P. Peterson 8, John M. Starr 15, Jessika E. Sussmann 4, Arthur W. Toga 1, Joanna M. Wardlaw 15, Margaret J. Wright 12, Hilleke E. Hulshoff Pol 5, Mark E. Bastin 4,15, Andrew M. McIntosh 4, Ian J. Deary 15, Paul M. Thompson 1* and David C. Glahn 3 JOIN US