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Transl Psychiatry. 2018 Jun 8;8(1):114. doi: 10.1038/s41398-018-0166-y.

Williams Syndrome neuroanatomical score associates with GTF2IRD1 in large-scale magnetic resonance imaging cohorts: a proof of concept for multivariate endophenotypes.

Author information

1
Department of Cognitive Science, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
2
Center for Multimodal Imaging and Genetics, School of Medicine, University of California San Diego, 9452 Medical Center Drive, La Jolla, CA, 92093, USA.
3
Institute for Biological Psychiatry, Mental Health Center Sct. Hans, Capital Region of Denmark, Roskilde, Denmark.
4
Department of Neurosciences, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92037, USA.
5
Center for Human Development, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
6
Department of Radiology, University of California San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA, 92037, USA.
7
NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, Norway.
8
Dr. E. Martens Research Group of Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
9
Department of Neuroscience, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
10
Department of Radiology, St. Olav University Hospital, Trondheim, Norway.
11
Department of Psychology, University of Oslo, Oslo, Norway.
12
NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
13
NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
14
Department of Psychiatry, University of California San Diego, La Jolla, School of Medicine, 9500 Gilman Drive, La Jolla, CA, 92037, USA.
15
Department of Neurosciences, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92037, USA. ehalgren@ucsd.edu.
16
Center for Human Brain Activity Mapping, University of California San Diego, School of Medicine, 3510 Dunhill Street, San Diego, CA, 92121, USA. ehalgren@ucsd.edu.

Abstract

Despite great interest in using magnetic resonance imaging (MRI) for studying the effects of genes on brain structure in humans, current approaches have focused almost entirely on predefined regions of interest and had limited success. Here, we used multivariate methods to define a single neuroanatomical score of how William's Syndrome (WS) brains deviate structurally from controls. The score is trained and validated on measures of T1 structural brain imaging in two WS cohorts (training, n = 38; validating, n = 60). We then associated this score with single nucleotide polymorphisms (SNPs) in the WS hemi-deleted region in five cohorts of neurologically and psychiatrically typical individuals (healthy European descendants, n = 1863). Among 110 SNPs within the 7q11.23 WS chromosomal region, we found one associated locus (p = 5e-5) located at GTF2IRD1, which has been implicated in animal models of WS. Furthermore, the genetic signals of neuroanatomical scores are highly enriched locally in the 7q11.23 compared with summary statistics based on regions of interest, such as hippocampal volumes (n = 12,596), and also globally (SNP-heritability = 0.82, se = 0.25, p = 5e-4). The role of genetic variability in GTF2IRD1 during neurodevelopment extends to healthy subjects. Our approach of learning MRI-derived phenotypes from clinical populations with well-established brain abnormalities characterized by known genetic lesions may be a powerful alternative to traditional region of interest-based studies for identifying genetic variants regulating typical brain development.

PMID:
29884845
PMCID:
PMC5993783
DOI:
10.1038/s41398-018-0166-y
[Indexed for MEDLINE]
Free PMC Article

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