Integrative analysis of genome-wide association studies identifies novel loci associated with neuropsychiatric disorders

Xueming Yao,Chonggui Zhu,Qianghua Xia,Xiaoyuan Hou,Joseph T Glessner,Heather S Hain,Liu Yang,Hakon Hakonarson,Xiaohui Qi,Frank D Mentch,Junyi Li,Jin Li,Michael E March,Xiaoge Li,Xinyi Meng

doi:10.1038/s41398-020-01195-5

Abstract

Neuropsychiatric disorders, such as autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), bipolar disorder (BIP), and major depressive disorder (MDD) share common clinical presentations, suggesting etiologic overlap. A substantial proportion of SNP-based heritability for neuropsychiatric disorders is attributable to genetic components, and genome-wide association studies (GWASs) focusing on individual diseases have identified multiple genetic loci shared between these diseases. Here, we aimed at identifying novel genetic loci associated with individual neuropsychiatric diseases and genetic loci shared by neuropsychiatric diseases. We performed multi-trait joint analyses and meta-analysis across five neuropsychiatric disorders based on their summary statistics from the Psychiatric Genomics Consortium (PGC), and further carried out a replication study of ADHD among 2726 cases and 16299 controls in an independent pediatric cohort. In the multi-trait joint analyses, we found five novel genome-wide significant loci for ADHD, one novel locus for BIP, and ten novel loci for MDD. We further achieved modest replication in our independent pediatric dataset. We conducted fine-mapping and functional annotation through an integrative multi-omics approach and identified causal variants and potential target genes at each novel locus. Gene expression profile and gene-set enrichment analysis further suggested early developmental stage expression pattern and postsynaptic membrane compartment enrichment of candidate genes at the genome-wide significant loci of these neuropsychiatric disorders. Therefore, through a multi-omics approach, we identified novel genetic loci associated with the five neuropsychiatric disorders which may help to better understand the underlying molecular mechanism of neuropsychiatric diseases.

Highlights

Neuropsychiatric disorders, such as autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), bipolar disorder (BIP), and major depressive disorder (MDD) are a spectrum of common, complex, polygenetic diseases[1,2,3,4]
Joint analysis of genome-wide association studies (GWASs) summary statistics To identify novel genetic factors associated with neuropsychiatric diseases, we conducted a multi-trait joint analysis based on summary statistics of the five neuropsychiatric GWASs of ADHD, ASD, BIP, MDD, and SCZ (Supplementary Table 1), taking phenotype correlation into account
We identified 16 novel genome-wide significant (GWS) loci, including 5 loci for ADHD, 1 for BIP, and 10 for MDD, which have not previously been reported to be associated with the corresponding neuropsychiatric disorder at the GWS level (Table 1, Supplementary Fig. 2, Supplementary Table 4)

Summary

Introduction

Neuropsychiatric disorders, such as autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), bipolar disorder (BIP), and major depressive disorder (MDD) are a spectrum of common, complex, polygenetic diseases[1,2,3,4]. Neuropsychiatric disorders have become a major public health concern. It is estimated that every year 38.2% of the European population (164.8 million persons) are suffering from a neuropsychiatric disorder[5]. Some neuropsychiatric disorders, such as the common childhood behavioral disorders ASD and ADHD, are characterized by the early age of onset[6,7]. One in 69 children aged 8 suffer from ASD6.

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Results

Conclusion