Article

Common genetic variants shared among five major psychiatric disorders: a large-scale genome-wide combined analysis

Lu Xia^1,2, Kun Xia^2,6, Daniel R Weinberger³, Fengyu Zhang^1,4,5*

¹Global Clinical and Translational Research Institute, Bethesda, MD, USA;

²Center for Medical Genetics & Hunan Key Laboratory for Medical Genetics, College of Life Sciences, the Central South University, Changsha, Hunan, China;

³Lieber Institute for Brain Development, Department of Psychiatry and Behavioral Sciences, Neurology, Neuroscience, Institute of Genomic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA;

⁴The Second Xiangya Hospital & National Clinical Research Center for Mental Health Deriders, Central South University, Changsha, Hunan, China;

⁵Peking University Huilongguan Clinical Medical School & Beijing Huilongguan Hospital, Beijing, China;

⁶Chinese Academy of Sciences Center for Excellence in Brain Science and Intelligences Technology (CENSIT), Shanghai, China.

Received February 7, 2019; Accepted February 27, 2019

ABSTRACT

Background: Genetic correlation and pleiotropic effects among psychiatric disorders have been reported. This study aimed to identify specific common genetic variants shared between five adult psychiatric disorders: schizophrenia, bipolar, major depressive disorder, attention deficit-hyperactivity disorder, and an autism spectrum disorder.

Methods: A combined p-value of about 8 million single nucleotide polymorphisms (SNPs) were calculated in an equivalent sample of 151,672 cases and 284,444 controls of European ancestry from published data based on the latest genome-wide association studies of five major psychiatric disorder using Stouffer's Z-score method. SNPs that achieved genome-wide significance (P<5x10^-08) were mapped to loci and genomic regions for further investigation; gene functional annotation and clustering were performed to understand the biological process and molecular function of the loci identified. We also examined CNVs and performed expression quantitative trait loci analysis for SNPs by genomic region.

Results: We find that 6,293 SNPs mapped to 336 loci are shared by the three adult psychiatric disorders, 1,108 variants at 73 loci are shared by the childhood disorders, and 713 variants at 47 genes are shared by all five disorders at genome-wide significance (p<5x10^-08). Of the 2,583 SNPs at the extended major histocompatibility complex identified for three adult dis-orders, none of them were associated with two childhood disorders; and SNPs shared by all five disorders were located in the regions that have been identified as containing copy number variation associated with autism and had largely neuro-developmental functions.

Conclusion: We show a number of specific SNPs associated with psychiatric disorders of childhood or adult-onset, illustrating not only genetic heterogeneity across these disorders but also developmental genes shared by them all. These results provide a manageable list of anchors from which to investigate epigenetic mechanism or gene-gene interaction on the development of neuropsychiatric disorders and for developing a measurement matrix for disease risk that could potentially be used for new taxonomy for precision medicine.

KEYWORDS

Psychiatric disorders; schizophrenia; bipolar disorder; major depressive disorder; attention deficit-hyperactivity disorder; autism spectrum disorder; genome-wide association study; combined analysis.

*Correspondence: Fengyu Zhang, zhangfy@gcatresearch.org, or Kun Xia, xiakun@sklmg.edu.cn

How to cite this article:

Xia, L, Xia, K, Weinberger, DR, Zhang F. Common genetic variants shared among major psychiatric disorders: A genome-wide combined analysis. Glob Clin Transl Res. 2019; 1(1):21-30. DOI:10.36316/gcatr.01.0003