Multi-Site Genetic Analysis of 1151 Diffusion MRI Scans from the

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

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

Meta analysis for genetic studiesImaging

Stein et al., 2012Bis et al., 2012, Ikram et al., 2012, Taal et al, 2012

26,000+ Images!

Genome-wide association study (GWAS)with imaging phenotypes

(ICV)

Genome-wide significancethreshold

Image courtesy of Dr. Jason Stein (that guy)

White Matter - Heritability, Risk GenesDTI

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

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

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/

• 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

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?

Let’s find out!• Multi-site heritability analysis

E C A A C E

Twin1 Twin2

ecaace

• 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).

ROI heritability results

Meta-analysis of heritability

Meta-analysis of heritability

Mega-analysis of heritability

SequentialOligogenic Linkage Analysis

Routines

N=1151

Single Site GWAS Q-Q plots

1. Preprocessing– Initial quality control– Creating FA maps

2. Registration to template and skeletonization– Intermediate QC– Projection distance

3. ROI extraction4. Final quality control

– Visual inspection of images– Histograms and outlier detection

5. GWAS / Other analysis

AcknowledgementsENIGMA DTI sites

Join ENIGMAhttp://enigma.loni.ucla.edu/members/join/Neda.Jahanshad@loni.ucla.edu

US/Australia/European funding agencies

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

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