Recent studies strongly suggest that there are common, genetically determined pathways to risk for psychiatric and neurodevelopmental disorders including autism, intellectual disability, attention deficit disorder, and schizophrenia, but no study has investigated the relationship between genetic variation and human brain development prior to the age at which clinical symptoms are first recognized. The primary objective of the current application is to use cutting-edge techniques in genomics to identify common and rare genetic variants which impact brain development in the early postnatal period, an extremely dynamic time which may be critical in the etiology of neurodevelopmental disorders. Intracranial volume (ICV), total white matter, total gray matter, lateral ventricle volume, and maturation of white matter tracts are heritable in neonates. The proposed project will test several major genetic mechanisms which could explain this high heritability. (1) We will test whether variation in structural brain phenotypes is predicted by common variants of moderate to large effect size by genotyping approximately 1 million single nucleotide polymorphisms (SNPs) and a genome-wide set of copy number variation (CNV) probes in a large (900 subject) and well-characterized population sample of children assessed with high-resolution MRI of the brain at 2 weeks of age with T1- weighted, T2-weighted, and diffusion tensor imaging sequences. Analysis will be completed in 2 stages, a hypothesis driven test of a defined set of genetic variants previously implicated in brain development and a hypothesis-generating unbiased search of the genome to identify previously unsuspected variants affecting brain development. (2) Using the same data set we will test whether variation in structural brain phenotypes is predicted by the combined effects of many common variants each with a small effect size through pathway analysis and advanced multi-marker association models. (3) We will also use this data set to test if the total burden of rare genic CNVs predicts variation in brain structure. (4) We will test whether rare SNPs and/or small insertions and deletions are associated with brain development by performing full exome sequencing in a subgroup of 20 children with enlarged ventricles, a phenotype which is highly relevant to neurodevelopmental disorders. While the focus of this grant is on the neonatal period, participants are also returning for follow-up scans and detailed developmental assessments at 1, 2, 4 and 6 yrs of age as part of 2 already funded studies. Thus, ultimately, the information generated in this grant can be used to study genetic determinates of the trajectories of structural and functional brain development across the critical transitional period of infancy and early childhood. This is an unprecedented opportunity to identify genetic variants which impact brain development, potentially mediating risk for psychiatric and neurodevelopmental disorders. A better understanding of such genetic mechanisms has the potential to inspire new approaches to prevention, diagnosis, and treatment which are urgently needed.
The primary goal of the current application is to identify common and rare genetic variants which predict early brain development in humans; a period which may be critical in the development of psychiatric and neurodevelopmental disorders such as autism, schizophrenia, intellectual disability and attention-deficit disorder. Results will significantly improve our understanding of how genes shape neurodevelopmental trajectories in a way which increases the risk for psychiatric and neurodevelopmental disorders. Ultimately, identifying the genes involved in brain development has the potential to significantly improve diagnosis, guide research efforts into environmental risk factors, and generate completely new treatment possibilities for individuals with psychiatric and neurodevelopmental conditions.
| Gilmore, John H; Knickmeyer, Rebecca C; Gao, Wei (2018) Imaging structural and functional brain development in early childhood. Nat Rev Neurosci 19:123-137 |
| Wang, Ching-Wei; Lee, Yu-Ching; Calista, Evelyne et al. (2018) A benchmark for comparing precision medicine methods in thyroid cancer diagnosis using tissue microarrays. Bioinformatics 34:1767-1773 |
| Kong, Dehan; Ibrahim, Joseph G; Lee, Eunjee et al. (2018) FLCRM: Functional linear cox regression model. Biometrics 74:109-117 |
| Zhao, Bingxin; Ibrahim, Joseph G; Li, Yun et al. (2018) Heritability of Regional Brain Volumes in Large-Scale Neuroimaging and Genetic Studies. Cereb Cortex : |
| Yu-Feng Liu, Leo; Liu, Yufeng; Zhu, Hongtu et al. (2018) SMAC: Spatial multi-category angle-based classifier for high-dimensional neuroimaging data. Neuroimage 175:230-245 |
| Zhang, Zhengwu; Descoteaux, Maxime; Zhang, Jingwen et al. (2018) Mapping population-based structural connectomes. Neuroimage 172:130-145 |
| Zhu, Wensheng; Yuan, Ying; Zhang, Jingwen et al. (2017) Genome-wide association analysis of secondary imaging phenotypes from the Alzheimer's disease neuroimaging initiative study. Neuroimage 146:983-1002 |
| Park, Yeonhee; Su, Zhihua; Zhu, Hongtu (2017) Groupwise envelope models for imaging genetic analysis. Biometrics 73:1243-1253 |
| Huang, Chao; Thompson, Paul; Wang, Yalin et al. (2017) FGWAS: Functional genome wide association analysis. Neuroimage 159:107-121 |
| Jha, Shaili C; Meltzer-Brody, Samantha; Steiner, Rachel J et al. (2016) Antenatal depression, treatment with selective serotonin reuptake inhibitors, and neonatal brain structure: A propensity-matched cohort study. Psychiatry Res Neuroimaging 253:43-53 |
Showing the most recent 10 out of 22 publications
