Multi-site genetic analysis of diffusion images and voxelwise heritability analysis: A pilot project of the ENIGMA-DTI working group
University of California, Los Angeles1, University of Maryland, Baltimore2, University of Edinburgh3, Yale University4, Utrecht University5, University of Warwick6, University of Oxford7, Texas Biomedical Research Institute8, University of Queensland9, Vanderbilt University10, QIMR Berghofer Medical Research Institute11, University of Texas Health Science Center at San Antonio12
TL;DR: The ENIGMA-DTI working group as mentioned in this paper analyzed high-resolution fractional anisotropy (FA) images from multiple imaging sites across North America, Australia, and Europe, to address the challenge of harmonizing imaging data collected at multiple sites.
About: This article is published in NeuroImage.The article was published on 2013-11-01 and is currently open access. It has received 327 citations till now. The article focuses on the topics: Fractional anisotropy & Imaging genetics.
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TL;DR: The pipeline is described in detail, following a brief overview of UK Biobank brain imaging and the acquisition protocol and several quantitative investigations carried out as part of the development of both the imaging protocol and the processing pipeline.
927 citations
TL;DR: The ENIGMA Consortium has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected.
Abstract: The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
713 citations
TL;DR: It is shown that the DTI measurements are highly site‐specific, highlighting the need of correcting for site effects before performing downstream statistical analyses, and that ComBat, a popular batch‐effect correction tool used in genomics, performs best at modeling and removing the unwanted inter‐site variability in FA and MD maps.
612 citations
TL;DR: The present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide, and is believed to be the first ever large-scale coordinated study of WM microstructural differences in schizophrenia.
Abstract: The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.
480 citations
TL;DR: Recent findings of connectomic studies in schizophrenia are discussed that examine how the disorder relates to disruptions of brain connectivity, including how brain disorders such as schizophrenia arise from abnormal brain network wiring and dynamics.
Abstract: Schizophrenia—a severe psychiatric condition characterized by hallucinations, delusions, loss of initiative and cognitive function—is hypothesized to result from abnormal anatomical neural connectivity and a consequent decoupling of the brain’s integrative thought processes. The rise of in vivo neuroimaging techniques has refueled the formulation of dysconnectivity hypotheses, linking schizophrenia to abnormal structural and functional connectivity in the brain at both microscopic and macroscopic levels. Over the past few years, advances in high-field structural and functional neuroimaging techniques have made it increasingly feasible to reconstruct comprehensive maps of the macroscopic neural wiring system of the human brain, know as the connectome. In parallel, advances in network science and graph theory have improved our ability to study the spatial and topological organizational layout of such neural connectivity maps in detail. Combined, the field of neural connectomics has created a novel platform that provides a deeper understanding of the overall organization of brain wiring, its relation to healthy brain function and human cognition, and conversely, how brain disorders such as schizophrenia arise from abnormal brain network wiring and dynamics. In this review we discuss recent findings of connectomic studies in schizophrenia that examine how the disorder relates to disruptions of brain connectivity.
415 citations
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