Multi-site study of additive genetic effects on fractional anisotropy of cerebral white matter: comparing meta
and mega analytical approaches for data pooling
Peter Kochunov(1)#, Neda Jahanshad(2,3)#, Emma Sprooten(4), Thomas E. Nichols(5, 6), René C. Mandl(7), Laura
Almasy(8), Tom Booth(9), Rachel M. Brouwer(7), Joanne E. Curran(8), Greig I. de Zubicaray(10), Rali Dimitrova(11),
Ravi Duggirala(8), Peter T. Fox(12), L. Elliot Hong(1), Bennett A. Landman(13), Hervé Lemaitre(14), Lorna Lopez
(9,15)
, Nicholas G. Martin (16), Katie L. McMahon(17), Braxton D. Mitchell(18), Rene L. Olvera (19), Charles P.
Peterson (8), John M. Starr (9,20), Jessika E. Sussmann(21), Arthur W. Toga(2), Joanna M. Wardlaw (13), Margaret J.
Wright(14), Susan N. Wright(1), Mark E. Bastin (13, 18), Andrew M. McIntosh(21), Dorret I Boomsma(22), René S.
Kahn(7), Anouk den Braber(22), Eco JC de Geus(22), Ian J. Deary(9), Hilleke E. Hulshoff Pol (7), Douglas
Williamson(19), John Blangero(8), Dennis van ’t Ent(22), Paul M. Thompson(2,3), and David C. Glahn(4)
# PK and NJ contributed equally to this work
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Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
Imaging Genetics Center, Institute of Neuroimaging Informatics, USC Keck School of Medicine, Los Angeles, CA, USA.
Department of Neurology, UCLA School of Medicine, Los Angeles, CA, USA.
Olin Neuropsychiatry Research Center in the Institute of Living, Yale University School of Medicine, New Haven, CT, USA.
Department of Statistics & Warwick Manufacturing Group, The University of Warwick, Coventry, UK.
Oxford Centre for Functional MRI of the Brain (FMRIB), Nuffield Department of Clinical Neurosciences, Oxford University, UK.
Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA.
Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, The University of Edinburgh, Edinburgh, UK
School of Psychology, University of Queensland, Brisbane, Australia.
Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK
Research Imaging Institute, University of Texas Health Science Center San Antonio, San Antonio, TX, USA.
Department of Electrical Engineering, Vanderbilt University, Nashville, TN, USA.
U1000 Research Unit Neuroimaging and Psychiatry, INSERM-CEA-Faculté de Médecine Paris-Sud. Orsay, France
Department of Psychology, The University of Edinburgh, Edinburgh, U.K.
Queensland Institute of Medical Research, Brisbane, Australia.
Center for Advanced Imaging, University of Queensland, Brisbane, Australia.
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
Department of Psychiatry, University of Texas Health Science Center San Antonio, San Antonio, TX, USA.
Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK
Department of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.
Department of Biological Psychology, VU University, Amsterdam, The Netherlands.
EMGO+ Institute, VU University Medical Center, Amsterdam, The Netherlands.
*Please address correspondence to:
Dr. Peter Kochunov
Maryland Psychiatric Research Center
Department of Psychiatry, University of Maryland, School of Medicine, Baltimore, MD, USA
Phone: (410) 402-6110
E-mail: pkochunov@mprc.umaryland.edu
Genetric analyses were performed for additional regions of interest to complete Johns Hopkins DTI
atlas-based estimates of heritability. Added regions assessed included the hippocampal part of the
cingulum (CGH), the fornix (cres) / stria terminalis (FXST) and the uncinate fasciculus (UNC).We
also evaluated the corpus callosum as a whole, combining the genu, body, and splenium. We
additionally broke apart the larger ROIs, specifically the corona radiata and the internal capsule into 3
comprising parts. The CR was divided into the anterior, posterior and superior regions (ACR, PCR and
SCR respectively). The IC was divided into the anterior limb (ALIC), posterior limb (PLIC), and the
retrolenticular part (RLIC).
Individual Site Heritability
1
0.9
0.8
0.7
0.6
GOBS
QTIM
0.5
TAOS
0.4
BrainSCALE
NTR
0.3
0.2
0.1
0
ACR
PCR
SCR ALIC PLIC RLIC
CC
CGH FXST UNC
As with the previous ROIs, we found variability in the heritability estimates by site. However all
regions seem stable in terms of high heritability. All cohorts showed significant heritability in all
regions after accounting for multiple comparisons, except for TAOS. TAOS only showed significant
heritability (p< 0.005) for the ARC and the CC. The UNC, despite its small size, showed consistently
high heritability estimates in all cohorts. The FXST region showed a more stable heritability estimate
than the FX assessed in the original analysis.