Journal Article

Expression quantitative trait loci in the developing human brain and their enrichment in neuropsychiatric disorders

Bray, Nicholas J., Toste, Carolina C., Hill, Matthew J., McLaughlin, Gemma, Hall, Lynsey S., Lewis, Cathryn M., Morgan, Joanne E., Hannon, Eilis, Mill, Jonathan, O’Donovan, Michael C., Robertson, Matthew J., Owen, Michael J., O’Brien, Heath E., Pardiñas, Antonio F., Schalkwyk, Leonard C.

2018

Overview

Background Genetic influences on gene expression in the human fetal brain plausibly impact upon a variety of postnatal brain-related traits, including susceptibility to neuropsychiatric disorders. However, to date, there have been no studies that have mapped genome-wide expression quantitative trait loci (eQTL) specifically in the human prenatal brain. Results We performed deep RNA sequencing and genome-wide genotyping on a unique collection of 120 human brains from the second trimester of gestation to provide the first eQTL dataset derived exclusively from the human fetal brain. We identify high confidence cis -acting eQTL at the individual transcript as well as whole gene level, including many mapping to a common inversion polymorphism on chromosome 17q21. Fetal brain eQTL are enriched among risk variants for postnatal conditions including attention deficit hyperactivity disorder, schizophrenia, and bipolar disorder. We further identify changes in gene expression within the prenatal brain that potentially mediate risk for neuropsychiatric traits, including increased expression of C4A in association with genetic risk for schizophrenia, increased expression of LRRC57 in association with genetic risk for bipolar disorder, and altered expression of multiple genes within the chromosome 17q21 inversion in association with variants influencing the personality trait of neuroticism. Conclusions We have mapped eQTL operating in the human fetal brain, providing evidence that these confer risk to certain neuropsychiatric disorders, and identifying gene expression changes that potentially mediate susceptibility to these conditions.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Animal Genetics and Genomics / Archives & records / Attention deficit hyperactivity disorder / Binding sites / Bioinformatics / Biomedical and Life Sciences / Bipolar disorder / Bipolar Disorder - genetics / Bipolar Disorder - pathology / Brain / Brain - embryology / Brain - metabolism / Brain mapping / Chromosome 17 / Chromosome Mapping / Chromosomes / Consortia / Data analysis / data collection / Deoxyribonucleic acid / DNA / DNA methylation / Evolutionary Biology / Female / Fetus - metabolism / Fetuses / Gene expression / Gene Expression Regulation / Gene mapping / Gene polymorphism / genes / Genetic Markers / Genetic Predisposition to Disease / Genome-Wide Association Study / Genomes / Genomics / Genotyping / Gestation / High-Throughput Nucleotide Sequencing / Human Genetics / Humans / Inversion / inversion polymorphism / Life Sciences / Male / Mental disorders / Microbial Genetics and Genomics / Neurosis / personality / Phenotype / Plant Genetics and Genomics / Polymorphism / Polymorphism, Single Nucleotide / pregnancy / Quality control / Quantitative Trait Loci / quantitative traits / Ribonucleic acid / risk / RNA / Schizophrenia / Schizophrenia - genetics / Schizophrenia - pathology / Stem cells / Studies / Transcription