Identifying the susceptibility genes and variants of neurodevelopmental and psychiatric diseases will not only contribute to our understanding of these diseases, but also point to potential therapeutic targets. Genome-wide association studies (GWAS) are commonly used to study complex diseases, including neuro-psychiatric diseases. Nevertheless, GWAS focus on common variants, and have not been successful in studying early- onset diseases, including many developmental disorders, whose risk alleles are generally kept at very low frequencies in population. Additionally, the results of GWAS often cannot be directly translated into knowledge of risk genes and disease mechanisms. The goal of this project is to develop comprehensive statistical methods for analyzing genetic data of neuropsychiatric diseases to map their susceptibility genes and gain insights of the disease genetics. (1) We propose methods to analyze exome and genome sequencing data from patient families. Unlike existing methods for genetic studies which often focus on type of data per time, our methods will integrate a broad spectrum of genetic variations at the level of genes, including non-synonymous and regulatory non-coding mutations, both de novo and inherited from parents in origin. This leads to a higher power of detecting risk genes. (2) Copy number variants (CNVs) make substantial contribution to neurodevelopmental disorders. But CNVs often overlap multiple genes and it is difficult to identify risk genes within disease-related CNVs. A new algorithm is proposed to extract gene-level information from CNVs. This allows us to combine CNV data and nucleotide variation data from sequencing, to better detect disease genes. (3) Importance of non-coding variants to complex disease has now been firmly established and expression QTL (eQTL) is a promising strategy to map non-coding variants that have functional effects on gene expression levels. We propose a novel statistical approach to joint analysis of eQTL and GWAS data. The method is unique in that it uses information of all eQTL of a gene to test its role in disease, including both cis- and trans-eQTL, across the entire range of effect sizes. (4) A key component of our effort is the integration of the methods we develop into user-friendly software that could benefit the broad psychiatric genetic community.

Public Health Relevance

Understanding genetics of neurodevelopmental and psychiatric diseases such as autism and schizophrenia will pave the way to better treatment of these complex and costly diseases. Sequencing or genotyping DNA of patients and their families provides a flood of data that can potentially reveal the genetic secrets of these diseases, yet, how to translate the data into knowledge of the underlying genes is challenging. The goal of this research is to develop a set of computational tools and software to interpret these large-scale genetic data from patients, facilitating the discovery of genes playing important roles in these diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH110531-01A1
Application #
9311685
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Arguello, Alexander
Project Start
2017-05-17
Project End
2020-02-28
Budget Start
2017-05-17
Budget End
2018-02-28
Support Year
1
Fiscal Year
2017
Total Cost
$577,659
Indirect Cost
$216,863
Name
University of Chicago
Department
Genetics
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637