Review

. 2017 Jan 15;145(Pt B):389-408.

doi: 10.1016/j.neuroimage.2015.11.057. Epub 2015 Dec 4.

ENIGMA and the individual: Predicting factors that affect the brain in 35 countries worldwide

Paul M Thompson¹, Ole A Andreassen², Alejandro Arias-Vasquez³, Carrie E Bearden⁴, Premika S Boedhoe⁵, Rachel M Brouwer⁶, Randy L Buckner⁷, Jan K Buitelaar⁸, Kazima B Bulayeva⁹, Dara M Cannon¹⁰, Ronald A Cohen¹¹, Patricia J Conrod¹², Anders M Dale¹³, Ian J Deary¹⁴, Emily L Dennis¹⁵, Marcel A de Reus⁶, Sylvane Desrivieres¹⁶, Danai Dima¹⁷, Gary Donohoe¹⁸, Simon E Fisher¹⁹, Jean-Paul Fouche²⁰, Clyde Francks¹⁹, Sophia Frangou²¹, Barbara Franke²², Habib Ganjgahi²³, Hugh Garavan²⁴, David C Glahn²⁵, Hans J Grabe²⁶, Tulio Guadalupe²⁷, Boris A Gutman¹⁵, Ryota Hashimoto²⁸, Derrek P Hibar¹⁵, Dominic Holland¹³, Martine Hoogman²⁹, Hilleke E Hulshoff Pol⁶, Norbert Hosten³⁰, Neda Jahanshad¹⁵, Sinead Kelly¹⁵, Peter Kochunov³¹, William S Kremen³², Phil H Lee³³, Scott Mackey³⁴, Nicholas G Martin³⁵, Bernard Mazoyer³⁶, Colm McDonald³⁷, Sarah E Medland³⁵, Rajendra A Morey³⁸, Thomas E Nichols³⁹, Tomas Paus⁴⁰, Zdenka Pausova⁴¹, Lianne Schmaal⁴², Gunter Schumann¹⁶, Li Shen⁴³, Sanjay M Sisodiya⁴⁴, Dirk J A Smit⁴⁵, Jordan W Smoller⁴⁶, Dan J Stein⁴⁷, Jason L Stein⁴⁸, Roberto Toro⁴⁹, Jessica A Turner⁵⁰, Martijn P van den Heuvel⁶, Odile L van den Heuvel⁵, Theo G M van Erp⁵¹, Daan van Rooij⁵², Dick J Veltman⁵, Henrik Walter⁵³, Yalin Wang⁵⁴, Joanna M Wardlaw⁵⁵, Christopher D Whelan¹⁵, Margaret J Wright⁵⁶, Jieping Ye⁵⁷; ENIGMA Consortium

Affiliations

¹ Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging & Informatics, Keck School of Medicine of the University of Southern California, Marina del Rey 90292, USA; Departments of Neurosciences, Radiology, Psychiatry, and Cognitive Science, University of California, San Diego 92093, CA, USA.
² NORMENT-KG Jebsen Centre, Institute of Clinical Medicine, University of Oslo, Oslo 0315, Norway; NORMENT-KG Jebsen Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo 0315, Norway.
³ Donders Center for Cognitive Neuroscience, Departments of Psychiatry, Human Genetics & Cognitive Neuroscience, Radboud University Medical Center, Nijmegen 6525, The Netherlands.
⁴ Department of Psychiatry & Biobehavioral Sciences, University of California, Los Angeles, CA 90095, USA; Dept. of Psychology, University of California, Los Angeles, CA 90095, USA; Brain Research Institute, University of California, Los Angeles, CA 90095, USA.
⁵ Department of Anatomy & Neurosciences, VU University Medical Center, Amsterdam, The Netherlands; Department of Psychiatry, VU University Medical Center (VUMC), Amsterdam, The Netherlands; Neuroscience Campus Amsterdam, VU/VUMC, Amsterdam, The Netherlands.
⁶ Brain Center Rudolf Magnus, Department of Psychiatry, UMC Utrecht, Utrecht 3584 CX, The Netherlands.
⁷ Department of Psychiatry, Massachusetts General Hospital, Boston 02114, USA.
⁸ Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6500 HB, The Netherlands; Department of Psychology, Center for Brain Science, Harvard University, Cambridge, MA 02138, USA.
⁹ N.I. Vavilov Institute of General Genetics, Russian Academy of Sciences, Gubkin str. 3, Moscow 119991, Russia.
¹⁰ National Institute of Mental Health Intramural Research Program, Bethesda 20892, USA; Neuroimaging & Cognitive Genomics Centre (NICOG), Clinical Neuroimaging Laboratory, NCBES Galway Neuroscience Centre, College of Medicine Nursing and Health Sciences, National University of Ireland Galway, H91 TK33 Galway, Ireland.
¹¹ Institute on Aging, University of Florida, Gainesville, FL 32611, USA.
¹² Department of Psychological Medicine and Psychiatry, Section of Addiction, King's College London, University of London, UK.
¹³ Departments of Neurosciences, Radiology, Psychiatry, and Cognitive Science, University of California, San Diego, La Jolla, CA 92093-0841, USA.
¹⁴ Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK.
¹⁵ Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging & Informatics, Keck School of Medicine of the University of Southern California, Marina del Rey 90292, USA.
¹⁶ MRC-SGDP Centre, Institute of Psychiatry, King's College London, London SE5 8AF, UK.
¹⁷ Institute of Psychiatry, Psychology and Neuroscience, King׳s College London, UK; Clinical Neuroscience Studies (CNS) Center, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, USA.
¹⁸ Neuroimaging and Cognitive Genomics center (NICOG), School of Psychology, National University of Ireland, Galway, Ireland.
¹⁹ Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen 6525 XD, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6500 HB, The Netherlands.
²⁰ Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
²¹ Clinical Neuroscience Studies (CNS) Center, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, USA.
²² Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525, The Netherlands; Department of Psychiatry, Radboud University Medical Center, Nijmegen 6525, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6500 HB, The Netherlands.
²³ Department of Statistics, The University of Warwick, Coventry, UK.
²⁴ Psychiatry Department, University of Vermont, VT, USA.
²⁵ Department of Psychiatry, Yale University, New Haven, CT 06511, USA; Olin Neuropsychiatric Research Center, Hartford, CT 06114, USA.
²⁶ Department of Psychiatry, University Medicine Greifswald, Greifswald 17489, Germany; Department of Psychiatry and Psychotherapy, HELIOS Hospital, Stralsund 18435, Germany.
²⁷ Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen 6525 XD, The Netherlands; International Max Planck Research School for Language Sciences, Nijmegen 6525 XD, The Netherlands.
²⁸ Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Japan.
²⁹ Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6500 HB, The Netherlands.
³⁰ Department of Radiology University Medicine Greifswald, Greifswald 17475, Germany.
³¹ Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
³² Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA.
³³ Center for Human Genetic Research, Massachusetts General Hospital, USA; Department of Psychiatry, Harvard Medical School, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, USA.
³⁴ Department of Psychiatry, University of Vermont, Burlington 05401, VT, USA.
³⁵ QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia.
³⁶ Groupe d'imagerie Neurofonctionnelle, UMR5296 CNRS CEA Université de Bordeaux, France.
³⁷ Neuroimaging & Cognitive Genomics Centre (NICOG), Clinical Neuroimaging Laboratory, NCBES Galway Neuroscience Centre, College of Medicine Nursing and Health Sciences, National University of Ireland Galway, H91 TK33 Galway, Ireland.
³⁸ Duke Institute for Brain Sciences, Duke University, NC 27710, USA.
³⁹ Department of Statistics & WMG, University of Warwick, Coventry CV4 7AL, UK; FMRIB Centre, University of Oxford, Oxford OX3 9DU, UK.
⁴⁰ Rotman Research Institute, Baycrest, Toronto, ON, Canada; Departments of Psychology and Psychiatry, University of Toronto, Toronto, Canada; Child Mind Institute, NY, USA.
⁴¹ The Hospital for Sick Children, University of Toronto, Toronto, Canada; Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto, Canada.
⁴² Department of Psychiatry, VU University Medical Center (VUMC), Amsterdam, The Netherlands; Neuroscience Campus Amsterdam, VU/VUMC, Amsterdam, The Netherlands.
⁴³ Center for Neuroimaging, Dept. of Radiology and Imaging Sciences, Indiana University School of Medicine, 355 W. 16th Street, Suite 4100, Indianapolis, IN 46202, USA; Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, 355 W. 16th Street, Suite 4100, Indianapolis, IN 46202, USA.
⁴⁴ Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London WC1N 3BG, UK and Epilepsy Society, Bucks, UK.
⁴⁵ Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands; Neuroscience Campus Amsterdam, VU/VUMC, Amsterdam, The Netherlands.
⁴⁶ Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, USA.
⁴⁷ Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa; MRC Research Unit on Anxiety & Stress Disorders, South Africa.
⁴⁸ Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging & Informatics, Keck School of Medicine of the University of Southern California, Marina del Rey 90292, USA; Neurogenetics Program, Department of Neurology, UCLA School of Medicine, Los Angeles 90095, USA.
⁴⁹ Institut Pasteur, Paris, 75015, France.
⁵⁰ Departments of Psychology and Neuroscience, Georgia State University, Atlanta, GA 30302, USA.
⁵¹ Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92617, USA.
⁵² Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6500 HB, The Netherlands.
⁵³ Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, CCM, Berlin 10117, Germany.
⁵⁴ School of Computing, Informatics and Decision Systems Engineering, Arizona State University, AZ 85281, USA.
⁵⁵ Brain Research Imaging Centre, University of Edinburgh, Edinburgh EH4 2XU, UK; Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH4 2XU, UK.
⁵⁶ Queensland Brain Institute, University of Queensland, Brisbane 4072, Australia.
⁵⁷ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI 48109, USA.

PMID: 26658930
PMCID: PMC4893347
DOI: 10.1016/j.neuroimage.2015.11.057

Review

ENIGMA and the individual: Predicting factors that affect the brain in 35 countries worldwide

Paul M Thompson et al. Neuroimage. 2017.

. 2017 Jan 15;145(Pt B):389-408.

doi: 10.1016/j.neuroimage.2015.11.057. Epub 2015 Dec 4.

Authors

Affiliations

¹ Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging & Informatics, Keck School of Medicine of the University of Southern California, Marina del Rey 90292, USA; Departments of Neurosciences, Radiology, Psychiatry, and Cognitive Science, University of California, San Diego 92093, CA, USA.
² NORMENT-KG Jebsen Centre, Institute of Clinical Medicine, University of Oslo, Oslo 0315, Norway; NORMENT-KG Jebsen Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo 0315, Norway.
³ Donders Center for Cognitive Neuroscience, Departments of Psychiatry, Human Genetics & Cognitive Neuroscience, Radboud University Medical Center, Nijmegen 6525, The Netherlands.
⁴ Department of Psychiatry & Biobehavioral Sciences, University of California, Los Angeles, CA 90095, USA; Dept. of Psychology, University of California, Los Angeles, CA 90095, USA; Brain Research Institute, University of California, Los Angeles, CA 90095, USA.
⁵ Department of Anatomy & Neurosciences, VU University Medical Center, Amsterdam, The Netherlands; Department of Psychiatry, VU University Medical Center (VUMC), Amsterdam, The Netherlands; Neuroscience Campus Amsterdam, VU/VUMC, Amsterdam, The Netherlands.
⁶ Brain Center Rudolf Magnus, Department of Psychiatry, UMC Utrecht, Utrecht 3584 CX, The Netherlands.
⁷ Department of Psychiatry, Massachusetts General Hospital, Boston 02114, USA.
⁸ Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6500 HB, The Netherlands; Department of Psychology, Center for Brain Science, Harvard University, Cambridge, MA 02138, USA.
⁹ N.I. Vavilov Institute of General Genetics, Russian Academy of Sciences, Gubkin str. 3, Moscow 119991, Russia.
¹⁰ National Institute of Mental Health Intramural Research Program, Bethesda 20892, USA; Neuroimaging & Cognitive Genomics Centre (NICOG), Clinical Neuroimaging Laboratory, NCBES Galway Neuroscience Centre, College of Medicine Nursing and Health Sciences, National University of Ireland Galway, H91 TK33 Galway, Ireland.
¹¹ Institute on Aging, University of Florida, Gainesville, FL 32611, USA.
¹² Department of Psychological Medicine and Psychiatry, Section of Addiction, King's College London, University of London, UK.
¹³ Departments of Neurosciences, Radiology, Psychiatry, and Cognitive Science, University of California, San Diego, La Jolla, CA 92093-0841, USA.
¹⁴ Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK.
¹⁵ Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging & Informatics, Keck School of Medicine of the University of Southern California, Marina del Rey 90292, USA.
¹⁶ MRC-SGDP Centre, Institute of Psychiatry, King's College London, London SE5 8AF, UK.
¹⁷ Institute of Psychiatry, Psychology and Neuroscience, King׳s College London, UK; Clinical Neuroscience Studies (CNS) Center, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, USA.
¹⁸ Neuroimaging and Cognitive Genomics center (NICOG), School of Psychology, National University of Ireland, Galway, Ireland.
¹⁹ Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen 6525 XD, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6500 HB, The Netherlands.
²⁰ Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
²¹ Clinical Neuroscience Studies (CNS) Center, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, USA.
²² Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525, The Netherlands; Department of Psychiatry, Radboud University Medical Center, Nijmegen 6525, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6500 HB, The Netherlands.
²³ Department of Statistics, The University of Warwick, Coventry, UK.
²⁴ Psychiatry Department, University of Vermont, VT, USA.
²⁵ Department of Psychiatry, Yale University, New Haven, CT 06511, USA; Olin Neuropsychiatric Research Center, Hartford, CT 06114, USA.
²⁶ Department of Psychiatry, University Medicine Greifswald, Greifswald 17489, Germany; Department of Psychiatry and Psychotherapy, HELIOS Hospital, Stralsund 18435, Germany.
²⁷ Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen 6525 XD, The Netherlands; International Max Planck Research School for Language Sciences, Nijmegen 6525 XD, The Netherlands.
²⁸ Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Japan.
²⁹ Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525, The Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6500 HB, The Netherlands.
³⁰ Department of Radiology University Medicine Greifswald, Greifswald 17475, Germany.
³¹ Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
³² Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA.
³³ Center for Human Genetic Research, Massachusetts General Hospital, USA; Department of Psychiatry, Harvard Medical School, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, USA.
³⁴ Department of Psychiatry, University of Vermont, Burlington 05401, VT, USA.
³⁵ QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia.
³⁶ Groupe d'imagerie Neurofonctionnelle, UMR5296 CNRS CEA Université de Bordeaux, France.
³⁷ Neuroimaging & Cognitive Genomics Centre (NICOG), Clinical Neuroimaging Laboratory, NCBES Galway Neuroscience Centre, College of Medicine Nursing and Health Sciences, National University of Ireland Galway, H91 TK33 Galway, Ireland.
³⁸ Duke Institute for Brain Sciences, Duke University, NC 27710, USA.
³⁹ Department of Statistics & WMG, University of Warwick, Coventry CV4 7AL, UK; FMRIB Centre, University of Oxford, Oxford OX3 9DU, UK.
⁴⁰ Rotman Research Institute, Baycrest, Toronto, ON, Canada; Departments of Psychology and Psychiatry, University of Toronto, Toronto, Canada; Child Mind Institute, NY, USA.
⁴¹ The Hospital for Sick Children, University of Toronto, Toronto, Canada; Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto, Canada.
⁴² Department of Psychiatry, VU University Medical Center (VUMC), Amsterdam, The Netherlands; Neuroscience Campus Amsterdam, VU/VUMC, Amsterdam, The Netherlands.
⁴³ Center for Neuroimaging, Dept. of Radiology and Imaging Sciences, Indiana University School of Medicine, 355 W. 16th Street, Suite 4100, Indianapolis, IN 46202, USA; Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, 355 W. 16th Street, Suite 4100, Indianapolis, IN 46202, USA.
⁴⁴ Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London WC1N 3BG, UK and Epilepsy Society, Bucks, UK.
⁴⁵ Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands; Neuroscience Campus Amsterdam, VU/VUMC, Amsterdam, The Netherlands.
⁴⁶ Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, USA.
⁴⁷ Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa; MRC Research Unit on Anxiety & Stress Disorders, South Africa.
⁴⁸ Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging & Informatics, Keck School of Medicine of the University of Southern California, Marina del Rey 90292, USA; Neurogenetics Program, Department of Neurology, UCLA School of Medicine, Los Angeles 90095, USA.
⁴⁹ Institut Pasteur, Paris, 75015, France.
⁵⁰ Departments of Psychology and Neuroscience, Georgia State University, Atlanta, GA 30302, USA.
⁵¹ Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92617, USA.
⁵² Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6500 HB, The Netherlands.
⁵³ Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, CCM, Berlin 10117, Germany.
⁵⁴ School of Computing, Informatics and Decision Systems Engineering, Arizona State University, AZ 85281, USA.
⁵⁵ Brain Research Imaging Centre, University of Edinburgh, Edinburgh EH4 2XU, UK; Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK; Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH4 2XU, UK.
⁵⁶ Queensland Brain Institute, University of Queensland, Brisbane 4072, Australia.
⁵⁷ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA; Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI 48109, USA.

PMID: 26658930
PMCID: PMC4893347
DOI: 10.1016/j.neuroimage.2015.11.057

Abstract

In this review, we discuss recent work by the ENIGMA Consortium (http://enigma.ini.usc.edu) - a global alliance of over 500 scientists spread across 200 institutions in 35 countries collectively analyzing brain imaging, clinical, and genetic data. Initially formed to detect genetic influences on brain measures, ENIGMA has grown to over 30 working groups studying 12 major brain diseases by pooling and comparing brain data. In some of the largest neuroimaging studies to date - of schizophrenia and major depression - ENIGMA has found replicable disease effects on the brain that are consistent worldwide, as well as factors that modulate disease effects. In partnership with other consortia including ADNI, CHARGE, IMAGEN and others¹, ENIGMA's genomic screens - now numbering over 30,000 MRI scans - have revealed at least 8 genetic loci that affect brain volumes. Downstream of gene findings, ENIGMA has revealed how these individual variants - and genetic variants in general - may affect both the brain and risk for a range of diseases. The ENIGMA consortium is discovering factors that consistently affect brain structure and function that will serve as future predictors linking individual brain scans and genomic data. It is generating vast pools of normative data on brain measures - from tens of thousands of people - that may help detect deviations from normal development or aging in specific groups of subjects. We discuss challenges and opportunities in applying these predictors to individual subjects and new cohorts, as well as lessons we have learned in ENIGMA's efforts so far.

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Figures

**Fig. 1**
Recent genome-wide association studies (GWAS) of brain disorders and brain structure. **Part A** shows the Manhattan plot from a 2014 *Nature* meta-analysis conducted by the Psychiatric Genomics Consortium. The genetic variants are presented on the x-axis, and the height of the dots shows the strength of association between each genetic variant and schizophrenia. A negative log p-value scale is used: higher points denote stronger associations. The group identified 108 schizophrenia-associated genetic loci in a sample of 34,241 cases and 45,604 controls (*red line* = genome-wide significance level, conventionally set at p = 5×10^–8; *green SNPs* = polymorphisms in linkage disequilibrium with index SNPs (diamonds), which indicate independent genome-wide significant signals). **Part B** 26 loci significantly associated with risk of Parkinson's Disease (Nalls et al., 2015), in 13,708 cases and 95,282 controls (*red SNPs* = genome-wide significant signals). **Part C** 19 loci significantly associated with risk of AD, in a sample of 17,008 cases and 37,154 controls (Lambert et al., *Nature Genetics*, 2013; genes identified by previous GWAS are shown in black; newly associated genes in red; red diamonds indicate SNPs with the smallest overall p-values in the analysis). **Part D** shows genome-wide associations for eight subcortical structures, conducted by the ENIGMA consortium in 30,717 individuals from 50 cohorts worldwide (Hibar et al., *Nature*, 2015). This study identified five novel genetic variants associated with differences in the volumes of the putamen and caudate nucleus and stronger evidence for three previously established influences on hippocampal volume (see Stein et al., *Nature Genetics*, 2012) and intracranial volume (see Ikram et al., *Nature Genetics*, 2012). Each Manhattan plot in Part D is color-coded to match its corresponding subcortical structure, shown in the middle row. The gray dotted line represents genome-wide significance at the standard p = 5×10^–8; the red dotted line shows a multiple-comparison corrected threshold of p = 7.1 × 10^–9. [Images are reproduced here with permission from MacMillan Publishers Ltd (*Nature Genetics*, 2012 & 2013; *Nature*, 2014 & 2015) and with permission from the corresponding authors.]

**Fig. 2. ENIGMA Map**
The ENIGMA consortium now consists of over 30 Working Groups made up of 500 scientists from over 200 institutions and 35 countries; several of these Working Groups have several ongoing secondary projects, led by different investigators. Here we show 12 of the working groups, focusing on specific diseases and methodologies, including ADHD, autism, addiction, bipolar disorder, diffusion tensor imaging, epilepsy, HIV, major depressive disorder, OCD, PTSD and schizophrenia. Centers where individuals are scanned and genotyped are denoted with color-coded pins (*legend, bottom left*).

**Fig. 3. ENIGMA Roadmap**
The current organization of ENIGMA's Working Groups is shown here. Several groups relate brain measures to variation in the genome, and specialized groups are dedicated to helping members run analyses of genome-wide SNP data, copy number variants, and epigenetic markers on the genome. In parallel, there are psychiatric and neurology working groups dedicated to the study of worldwide data from a range of diseases. As shown here in detail for the schizophrenia working group, there are secondary projects, to relate brain variation to specific symptoms or clinical measures. In parallel, support groups coordinate large scale efforts to harmonize DTI (diffusion tensor imaging) and related brain data (Jahanshad et al., 2014). Partnerships between the DTI and Genomics groups are leading to genome-wide screens of DTI measures in over 13,000 people; cross-disorder partnerships study brain features that may relate to diagnostic boundaries, or common co-morbidities, allowing factors driving brain variations to be disentangled.

**Fig. 4**
ENIGMA's studies of brain differences in disease revealed consistent patterns of subcortical volume differences across multiple cohorts with schizophrenia and major depression (data reproduced, with permission, from van Erp et al., 2015; Schmaal et al., 2015, *Molecular Psychiatry*). Here we show the effect sizes (Cohen's d), for the mean volume difference between patients and matched controls, for a range of brain structures measured from MRI. After meta-analysis of all cohorts, in schizophrenia, a range of subcortical structures showed volumetric differences, including hypertrophy, which may be due in part to antipsychotic treatment. In major depression, the hippocampus is smaller in the depressed groups. Such data, for these and other brain measures, is now being compiled and analyzed across 12 disorders in ENIGMA (see Table 1 for a summary), and may be useful for classification, so long as relevant confounds, site effects, and co-morbidities are appropriately modeled and understood.

**Fig. 5. Meta-Analyzing Statistical Brain Maps**
As in other fields of brain mapping, voxel-based statistical analyses can map statistical associations between predictors and brain signals. To meta-analyze maps of statistical associations across sites, Jahanshad et al. (2015a,, proposed a method whereby each site aligns data to their own brain template (mean deformation template, or MDT). Statistics from each site are meta-analyzed at each voxel, after a second round of registration to an overall mean template (computed here from 4 cohorts representing different parts of the lifespan). Analyses proceed in parallel, using computational resources across all sites; analyses are updated when a new site joins. This approach applies equally to voxel-based maps of function, and the ENIGMA-Shape working group has modified it to work with surface-based coordinates (Gutman et al., 2015a,b,c). If structural labels are used to drive the multi-channel registration (*top panels*), in conjunction with an approach such as tensor-based morphometry, the resulting local volumetric measures should closely mirror volumetric findings for specific regions of interest. As such, some results of brain-wide genome-wide searches can be checked by consulting genome-wide association results for specific regions of interest (Hibar et al., 2015a,; Adams and the CHARGE and ENIGMA2 Consortia, submitted for publication).

See this image and copyright information in PMC

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ENIGMA and the individual: Predicting factors that affect the brain in 35 countries worldwide

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ENIGMA and the individual: Predicting factors that affect the brain in 35 countries worldwide

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