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

Published on Jun 8, 2018in Translational Psychiatry5.28
· DOI :10.1038/S41398-018-0166-Y
Chun Chieh Fan26
Estimated H-index: 26
(UCSD: University of California, San Diego),
Andrew J. Schork35
Estimated H-index: 35
+ 13 AuthorsEric Halgren87
Estimated H-index: 87
(UCSD: University of California, San Diego)
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.
📖 Papers frequently viewed together
1 Citations
17 Authors (Li Shen, ..., Andrew J. Saykin)
340 Citations
10 Authors (Natalie Cope, ..., Jeffrey R. Gruen)
47 Citations
#1Bridgett M. vonHoldt (Princeton University)H-Index: 28
#2Emily Shuldiner (Princeton University)H-Index: 1
Last. Monique A. R. Udell (OSU: Oregon State University)H-Index: 14
view all 12 authors...
Although considerable progress has been made in understanding the genetic basis of morphologic traits (for example, body size and coat color) in dogs and wolves, the genetic basis of their behavioral divergence is poorly understood. An integrative approach using both behavioral and genetic data is required to understand the molecular underpinnings of the various behavioral characteristics associated with domestication. We analyze a 5-Mb genomic region on chromosome 6 previously found to be under...
68 CitationsSource
#1Evan A. Boyle (Stanford University)H-Index: 24
#2Yang I. Li (Stanford University)H-Index: 29
Last. Jonathan K. Pritchard (Stanford University)H-Index: 95
view all 3 authors...
A central goal of genetics is to understand the links between genetic variation and disease. Intuitively, one might expect disease-causing variants to cluster into key pathways that drive disease etiology. But for complex traits, association signals tend to be spread across most of the genome—including near many genes without an obvious connection to disease. We propose that gene regulatory networks are sufficiently interconnected such that all genes expressed in disease-relevant cells are liabl...
1,328 CitationsSource
#1Chun Chieh Fan (UCSD: University of California, San Diego)H-Index: 26
#2Timothy T. Brown (UCSD: University of California, San Diego)H-Index: 34
Last. Anders M. DaleH-Index: 166
view all 10 authors...
Abstract Williams Syndrome (WS) is a rare genetic disorder with unique behavioral features. Yet the rareness of WS has limited the number and type of studies that can be conducted in which inferences are made about how neuroanatomical abnormalities mediate behaviors. In this study, we extracted a WS-specific neuroanatomical profile from structural magnetic resonance imaging (MRI) measurements and tested its association with behavioral features of WS. Using a WS adult cohort (22 WS, 16 healthy co...
15 CitationsSource
#1Thanathom Chailangkarn (UCSD: University of California, San Diego)H-Index: 8
#2Cleber A. Trujillo (UCSD: University of California, San Diego)H-Index: 21
Last. Alysson R. Muotri (UCSD: University of California, San Diego)H-Index: 58
view all 28 authors...
A human neurodevelopmental model fills the current knowledge gap in the cellular biology of Williams syndrome and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain.
107 CitationsSource
#1Susan M. Corley (UNSW: University of New South Wales)H-Index: 7
#2Cesar P. Canales (UNSW: University of New South Wales)H-Index: 7
Last. Stephen J. Palmer (UNSW: University of New South Wales)H-Index: 13
view all 8 authors...
Background Williams-Beuren Syndrome (WBS) is a genetic disorder associated with multisystemic abnormalities, including craniofacial dysmorphology and cognitive defects. It is caused by a hemizygous microdeletion involving up to 28 genes in chromosome 7q11.23. Genotype/phenotype analysis of atypical microdeletions implicates two evolutionary-related transcription factors, GTF2I and GTF2IRD1, as prime candidates for the cause of the facial dysmorphology.
6 CitationsSource
#1Kristine B. Walhovd (University of Oslo)H-Index: 75
#2Anders M. Fjell (University of Oslo)H-Index: 76
Last. Timothy T. Brown (UCSD: University of California, San Diego)H-Index: 34
view all 5 authors...
Understanding how brain development normally proceeds is a premise of understanding neurodevelopmental disorders. This has sparked awealth of magnetic resonance imaging (MRI)studies. Unfortunately, theyare in marked disagreementon how the cerebral cortex matures. While cortical thickness increases for the first 8–9 years of life have repeatedly been reported, others find continuous cortical thinning from early childhood, at least from age 3 or 4 years. We review these inconsistencies, and discus...
135 CitationsSource
#1Terry L. Jernigan (UCSD: University of California, San Diego)H-Index: 101
#2Timothy T. Brown (UCSD: University of California, San Diego)H-Index: 34
Last. Anders M. Dale (UCSD: University of California, San Diego)H-Index: 166
view all 27 authors...
The main objective of the multi-site Pediatric Imaging, Neurocognition, and Genetics (PING) study was to create a large repository of standardized measurements of behavioral and imaging phenotypes accompanied by whole genome genotyping acquired from typically-developing children varying widely in age (3 to 20 years). This cross-sectional study produced sharable data from 1493 children, and these data have been described in several publications focusing on brain and cognitive development. Researc...
167 CitationsSource
#1Paulina Carmona-Mora (UNSW: University of New South Wales)H-Index: 9
#2Jocelyn Widagdo (UQ: University of Queensland)H-Index: 13
Last. Stephen J. Palmer (UNSW: University of New South Wales)H-Index: 13
view all 11 authors...
GTF2IRD1 is one of the three members of the GTF2I gene family, clustered on chromosome 7 within a 1.8 Mb region that is prone to duplications and deletions in humans. Hemizygous deletions cause Williams–Beuren syndrome (WBS) and duplications cause WBS duplication syndrome. These copy number variations disturb a variety of developmental systems and neurological functions. Human mapping data and analyses of knockout mice show that GTF2IRD1 and GTF2I underpin the craniofacial abnormalities, mental ...
12 CitationsSource
#1Chun Chieh Fan (UCSD: University of California, San Diego)H-Index: 26
#2Hauke Bartsch (UCSD: University of California, San Diego)H-Index: 27
Last. Anders M. DaleH-Index: 166
view all 12 authors...
Summary Knowing how the human brain is shaped by migration and admixture is a critical step in studying human evolution [1, 2], as well as in preventing the bias of hidden population structure in brain research [3, 4]. Yet, the neuroanatomical differences engendered by population history are still poorly understood. Most of the inference relies on craniometric measurements, because morphology of the brain is presumed to be the neurocranium's main shaping force before bones are fused and ossified...
22 CitationsSource
#1Chi-Hua Chen (UCSD: University of California, San Diego)H-Index: 34
#2Qian Peng (Scripps Research Institute)H-Index: 10
Last. John K. Hsiao (NIH: National Institutes of Health)H-Index: 48
view all 22 authors...
Little is known about how genetic variation contributes to neuroanatomical variability, and whether particular genomic regions comprising genes or evolutionarily conserved elements are enriched for effects that influence brain morphology. Here, we examine brain imaging and single-nucleotide polymorphisms (SNPs) data from B2,700 individuals. We show that a substantial proportion of variation in cortical surface area is explained by additive effects of SNPs dispersed throughout the genome, with a ...
29 CitationsSource
Cited By3
#1Chun Chieh Fan (UCSD: University of California, San Diego)H-Index: 26
#2R. J. Loughnan (UCSD: University of California, San Diego)H-Index: 4
Last. Anders M. Dale (UCSD: University of California, San Diego)H-Index: 166
view all 0 authors...
It is important to understand the molecular determinants for microstructures of human brain. However, past genome-wide association studies (GWAS) on microstructures of human brain have had limited results due to methodological constraints. Here, we adopt advanced imaging processing methods and multivariate GWAS on two large scale imaging genetic datasets (UK Biobank and Adolescent Brain Cognitive Development study) to identify and validate key genetic association signals. We discovered 503 uniqu...
#1Clara MoreauH-Index: 8
#2Christopher R.K. Ching (SC: University of Southern California)H-Index: 25
Last. Carrie E. Bearden (Semel Institute for Neuroscience and Human Behavior)H-Index: 79
view all 5 authors...
Copy Number Variants (CNVs) are associated with elevated rates of neuropsychiatric disorders. A ‘genetics-first’ approach, involving the CNV effects on the brain, irrespective of clinical symptomatology, allows investigation of mechanisms underlying neuropsychiatric disorders in the general population. Recent years have seen an increasing number of larger multisite neuroimaging studies investigating the effect of CNVs on structural and functional brain endophenotypes. Alterations overlap with th...
#1van der Meer (University of Oslo)H-Index: 1
#1Dennis van der Meer (University of Oslo)H-Index: 20
Last. DaleH-Index: 1
view all 17 authors...
The folding of the human cerebral cortex is a highly genetically regulated process that allows for a much larger surface area to fit into the cranial vault and optimizes functional organization. Sulcal depth is a robust, yet understudied measure of localized folding, previously associated with a range of neurodevelopmental disorders. Here, we report the first genome-wide association study of sulcal depth. Through the Multivariate Omnibus Statistical Test (MOSTest) applied to vertex-wise measures...
1 CitationsSource
#1Ikuo Otsuka (Kobe University)H-Index: 9
#2Masato Akiyama (Kyushu University)H-Index: 23
Last. Akitoyo Hishimoto (Kobe University)H-Index: 18
view all 16 authors...
Suicide is a significant public health problem worldwide, and several Asian countries including Japan have relatively high suicide rates on a world scale. Twin, family, and adoption studies have suggested high heritability for suicide, but genetics lags behind due to difficulty in obtaining samples from individuals who died by suicide, especially in non-European populations. In this study, we carried out genome-wide association studies combining two independent datasets totaling 746 suicides and...
12 CitationsSource