title: Multi-site study of additive genetic effects on fractional anisotropy of cerebral white matter: Comparing meta and megaanalytical approaches for data pooling.
abstract: Combining datasets across independent studies can boost statistical power by increasing the numbers of observations and can achieve more accurate estimates of effect sizes. This is especially important for genetic studies where a large number of observations are required to obtain sufficient power to detect and replicate genetic effects. There is a need to develop and evaluate methods for joint-analytical analyses of rich datasets collected in imaging genetics studies. The ENIGMA-DTI consortium is developing and evaluating approaches for obtaining pooled estimates of heritability through meta-and mega-genetic analytical approaches, to estimate the general additive genetic contributions to the intersubject variance in fractional anisotropy (FA) measured from diffusion tensor imaging (DTI). We used the ENIGMA-DTI data harmonization protocol for uniform processing of DTI data from multiple sites. We evaluated this protocol in five family-based cohorts providing data from a total of 2248 children and adults (ages: 9-85) collected with various imaging protocols. We used the imaging genetics analysis tool, SOLAR-Eclipse, to combine twin and family data from Dutch, Australian and Mexican-American cohorts into one large "mega-family". We showed that heritability estimates may vary from one cohort to another. We used two meta-analytical (the sample-size and standard-error weighted) approaches and a mega-genetic analysis to calculate heritability estimates across-population. We performed leave-one-out analysis of the joint estimates of heritability, removing a different cohort each time to understand the estimate variability. Overall, meta- and mega-genetic analyses of heritability produced robust estimates of heritability.
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA. Electronic address: pkochunov@mprc.umaryland.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Kochunov
authors.affiliation: Imaging Genetics Center, Institute of Neuroimaging and Informatics, Department of Neurology, Keck School of Medicine of USC, Los Angeles, CA, USA.
authors.forename: Neda
authors.initials: N
authors.lastname: Jahanshad
authors.affiliation: Olin Neuropsychiatry Research Center in the Institute of Living, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Emma
authors.initials: E
authors.lastname: Sprooten
authors.affiliation: 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.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Nichols
authors.affiliation: Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: René C
authors.initials: RC
authors.lastname: Mandl
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Almasy
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, The University of Edinburgh, Edinburgh, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Booth
authors.affiliation: Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Brouwer
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA.
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Curran
authors.affiliation: School of Psychology, University of Queensland, Brisbane, Australia.
authors.forename: Greig I
authors.initials: GI
authors.lastname: de Zubicaray
authors.affiliation: Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.
authors.forename: Rali
authors.initials: R
authors.lastname: Dimitrova
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Duggirala
authors.affiliation: Research Imaging Institute, University of Texas Health Science Center San Antonio, San Antonio, TX, USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Fox
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: L Elliot
authors.initials: LE
authors.lastname: Hong
authors.affiliation: Department of Electrical Engineering, Vanderbilt University, Nashville, TN, USA.
authors.forename: Bennett A
authors.initials: BA
authors.lastname: Landman
authors.affiliation: U1000 Research Unit Neuroimaging and Psychiatry, INSERM-CEA-Faculté de Médecine Paris-Sud, Orsay, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Lemaitre
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, The University of Edinburgh, Edinburgh, UK.
authors.forename: Lorna M
authors.initials: LM
authors.lastname: Lopez
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: Centre for Advanced Imaging, University of Queensland, Brisbane, Australia.
authors.forename: Katie L
authors.initials: KL
authors.lastname: McMahon
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Braxton D
authors.initials: BD
authors.lastname: Mitchell
authors.affiliation: Department of Psychiatry, University of Texas Health Science Center San Antonio, San Antonio, TX, USA.
authors.forename: Rene L
authors.initials: RL
authors.lastname: Olvera
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Peterson
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, The University of Edinburgh, Edinburgh, UK; Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.
authors.forename: John M
authors.initials: JM
authors.lastname: Starr
authors.affiliation: Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.
authors.forename: Jessika E
authors.initials: JE
authors.lastname: Sussmann
authors.affiliation: Imaging Genetics Center, Institute of Neuroimaging and Informatics, Department of Neurology, Keck School of Medicine of USC, Los Angeles, CA, USA.
authors.forename: Arthur W
authors.initials: AW
authors.lastname: Toga
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, The University of Edinburgh, Edinburgh, UK; Brain Research Imaging Centre, Centre for Clinical Brain Sciences, University of Edinburgh, UK.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Wardlaw
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Wright
authors.affiliation: Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Susan N
authors.initials: SN
authors.lastname: Wright
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, The University of Edinburgh, Edinburgh, UK; Brain Research Imaging Centre, Centre for Clinical Brain Sciences, University of Edinburgh, UK.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Bastin
authors.affiliation: Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: McIntosh
authors.affiliation: Department of Biological Psychology, VU University, Amsterdam, The Netherlands.
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.affiliation: Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: René S
authors.initials: RS
authors.lastname: Kahn
authors.affiliation: Department of Biological Psychology, VU University, Amsterdam, The Netherlands.
authors.forename: Anouk
authors.initials: A
authors.lastname: den Braber
authors.affiliation: Department of Biological Psychology, VU University, Amsterdam, The Netherlands.
authors.forename: Eco J C
authors.initials: EJ
authors.lastname: de Geus
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, The University of Edinburgh, Edinburgh, UK.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Deary
authors.affiliation: Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Hilleke E
authors.initials: HE
authors.lastname: Hulshoff Pol
authors.affiliation: Department of Psychiatry, University of Texas Health Science Center San Antonio, San Antonio, TX, USA.
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Williamson
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA.
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.affiliation: Department of Biological Psychology, VU University, Amsterdam, The Netherlands.
authors.forename: Dennis
authors.initials: D
authors.lastname: van 't Ent
authors.affiliation: Imaging Genetics Center, Institute of Neuroimaging and Informatics, Department of Neurology, Keck School of Medicine of USC, Los Angeles, CA, USA; Department of Neurology, Pediatrics, Engineering, Psychiatry, Radiology, & Ophthalmology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Thompson
authors.affiliation: Olin Neuropsychiatry Research Center in the Institute of Living, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Glahn
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016880:Anisotropy; D001921:Brain; D002648:Child; D056324:Diffusion Tensor Imaging; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D066127:White Matter; D055815:Young Adult
keywords: Diffusion tensor imaging (DTI); Heritability; Imaging genetics; Meta-analysis; Multi-site; Reliability