Genetic architecture of the human brain and neuropsychiatric disorders

人脑的遗传结构和神经精神疾病

• 批准号: 10519107
• 负责人: Chi-Hua Chen
• 金额: $ 53.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-03 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10519107
• 关键词: Affect; Age; Aging; Area; Atlases; Brain; Brain Diseases; Brain imaging; Brain region; Clinical; Data; Databases; Development; Diagnosis; Diagnostic; Diffusion; Disease; Drug Targeting; Early Diagnosis; Early Intervention; Elements; Environmental Exposure; Environmental Risk Factor; Failure; Fiber; Functional Imaging; Genes; Genetic; Genetic Epistasis; Genetic Heterogeneity; Genetic Models; Genetic Risk; Genetic Variation; Genomic Segment; Genomics; Genotype; Goals; Hereditary Disease; Heritability; Heterogeneity; Human; Imaging technology; Incidence; Individual; Knowledge; Link; Longevity; Magnetic Resonance Imaging; Maps; Measures; Medicine; Mental disorders; Methods; Modeling; Molecular; Multimodal Imaging; Neurologic; Neurologic Symptoms; Pathogenicity; Pattern; Phenotype; Population; Population Heterogeneity; Prevention; Primates; Research; Resources; Risk; Sampling; Single Nucleotide Polymorphism; Source; Specific qualifier value; Structure; Subgroup; Surface; Testing; Therapeutic; Thick; Translating; Twin Multiple Birth; Variant; Work; aging brain; base; biobank; brain abnormalities; brain behavior; brain magnetic resonance imaging; cohort; drug development; frontal lobe; gene environment interaction; gene interaction; genetic architecture; genetic signature; genetic variant; genome wide association study; genome-wide analysis; gray matter; high risk; imaging genetics; imaging modality; improved; in vivo; individual variation; insight; nervous system disorder; neurodevelopment; neuropsychiatric disorder; neuropsychiatry; novel; novel therapeutics; pleiotropism; polygenic risk score; precision medicine; pressure; prevent; psychiatric symptom; risk variant; schizophrenia risk; sex; success; therapeutic development; therapy development; trait; transcriptome; white matter

Project Summary Our goal is to determine gene-brain-behavior relationships, including those that underlie neuropsychiatric disorders. These disorders are common and increasing in incidence worldwide. However, there are significant clinical gaps in current treatment and objective diagnosis. Drug development trial failure rates are disproportionately high for brain disorders due to largely unknown differences in genetic bases between model species’ and human’s brains, which prevent translational success. A major challenge hindering progress in neuropsychiatric medicine is our limited understanding of the genetics underlying the complexity of human brain structure and function. Our first objective in the current study is to uncover genetic variants associated with brain imaging phenotypes (Aim 1). Our second objective is to test the genetic effects of regulatory and phylogenically annotated genomic elements on the human brain (Aim 2). Our third objective is to determine the impact of neuropsychiatric genetic risks and their environmental interactions on the brain (Aim 3). Previously we produced the first genetic atlas of the human cortex based on magnetic resonance imaging (MRI) data of twins using fuzzy clustering. This work not only confirmed that human brain phenotypes are heritable traits but also demonstrated a clear region-specific genetic pattern, which facilitates identification of genetic variants associated with brain subdivisions. Our recent work demonstrated the value of using this atlas to determine the segments of the genome that are enriched for genetic effects influencing brain structure. In this proposal, we will leverage a ten-fold enlarged sample with both MRI and single nucleotide polymorphism (SNP) data, and advanced genetic and imaging methods to significantly expand the scope of our work. The larger sample increases power for discovering SNPs associated with individual brain structures and will enable us to examine genetic heterogeneity by age, sex, and genetic ancestries. Characterizing subgroups is critical for precision medicine approaches and to increase statistical power using genetically more homogeneous groups (Aim 1). We will also characterize pleiotropy and regulatory epistasis effects on the brain by multimodal imaging (structural, diffusion and functional imaging). This will provide insight into shared and distinct genetic influences among different brain regions. We hypothesize that variations in the highly expanded human cortex are associated with regulatory genetic effects (Aim 2). Third, building on improved genetic knowledge of the brain, we will determine its genetic relationship with neuropsychiatric disorders. We will estimate effects of psychiatric and neurological genetic risks and environmental exposures on deviations of MRI phenotypes from normal neurodevelopmental and aging trajectories (Aim 3). The current project has strong potential to significantly increase our understanding of genetic basis of the human brain, and to determine genetic and environmental factors that drive brain deviations from typical trajectories across lifespan, with a long-term goal to ultimately improve diagnostics, early intervention and therapeutic development for neuropsychiatric disorders.

项目总结

项目成果

Atypical genomic cortical patterning in autism with poor early language outcome.

• DOI: 10.1126/sciadv.abh1663
• 发表时间: 2021-09-03
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Lombardo MV;Eyler L;Pramparo T;Gazestani VH;Hagler DJ Jr;Chen CH;Dale AM;Seidlitz J;Bethlehem RAI;Bertelsen N;Barnes CC;Lopez L;Campbell K;Lewis NE;Pierce K;Courchesne E
• 通讯作者: Courchesne E

Candidates for drug repurposing to address the cognitive symptoms in schizophrenia.

重新调整药物用途以解决精神分裂症认知症状的候选者。

• DOI: 10.1016/j.pnpbp.2022.110637
• 发表时间: 2023
• 期刊: Progress in neuro-psychopharmacology & biological psychiatry
• 影响因子: 5.6
• 作者: Koch,Elise;Kauppi,Karolina;Chen,Chi-Hua
• 通讯作者: Chen,Chi-Hua

Discovery of genomic loci of the human cerebral cortex using genetically informed brain atlases.

• DOI: 10.1126/science.abe8457
• 发表时间: 2022-02-04
• 期刊: Science (New York, N.Y.)

Chromosomal inversion polymorphisms shape human brain morphology.

• DOI: 10.1016/j.celrep.2023.112896
• 发表时间: 2023-08-29
• 期刊: Cell reports
• 影响因子: 8.8

Larger cerebral cortex is genetically correlated with greater frontal area and dorsal thickness.

较大的大脑皮层在遗传上与较大的额叶区域和背侧厚度相关。

• DOI: 10.1073/pnas.2214834120
• 发表时间: 2023-03-14
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Makowski, Carolina;Wang, Hao;Srinivasan, Anjali;Qi, Anna;Qiu, Yuqi;van der Meer, Dennis;Frei, Oleksandr;Zou, Jingjing;Visscher, Peter M.;Yang, Jian;Chen, Chi-Hua
• 通讯作者: Chen, Chi-Hua