Genome-Wide Analysis Reveals Four Novel Loci for Attention-Deficit Hyperactivity Disorder in Korean Youths

Abstract

Attention-deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, and affects 5-8% of children worldwide. 1) ADHD is associated with academic under-achievement and dysfunctional relationships with family members and peers. 2) It is a heterogeneous and complex disorder, and its pathophysiology remains largely unknown.Previous twin and adoption studies have suggested a strong genetic contribution to ADHD, and a meta-analysis of twin studies has reported an average heritability of 76%. 3) Several candidate gene association studies have investigated ADHD risk genes, including dopamine-related genes (DRD4, DRD5, and SLC6AC), serotonin-related genes (HTR1B and SLC6A4), and synaptic vesicle fusion-related gene SNAP-25. 4) However, efforts to replicate these results have been inconsistent. 5) Furthermore, many common gene variants with small effects are considered to contribute to ADHD. 3)Genome-wide association studies (GWAS) are powerful tools for detecting, at several hundred thousand positions in the genome, common genetic polymorphisms that influence disease susceptibility and quantitative traits. Numerous GWAS have been conducted to identify ADHD risk loci using either case-control or family-based designs, 4) and a recent meta-This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Objectives:The molecular mechanisms underlying attention-deficit hyperactivity disorder (ADHD) remain unclear. Therefore, this study aimed to identify the genetic susceptibility loci for ADHD in Korean children with ADHD. We performed a case-control and a family-based genome-wide association study (GWAS), as well as genome-wide quantitative trait locus (QTL) analyses, for two symptom traits. Methods: A total of 135 subjects (71 cases and 64 controls), for the case-control analysis, and 54 subjects (27 probands and 27 unaffected siblings), for the family-based analysis, were included. Results: The genome-wide QTL analysis identified four single nucleotide polymorphisms (SNPs) (rs7684645 near APELA, rs12538843 near YAE1D1 and POU6F2, rs11074258 near MCTP2, and rs34396552 near CIDEA) that were significantly associated with the number of inattention symptoms in ADHD. These SNPs showed possible association with ADHD in the family-based GWAS, and with hyperactivity-impulsivity in genome-wide QTL analyses. Moreover, association signals in the family-based QTL analysis for the number of inattention symptoms were clustered near genes IL10, IL19, SCL5A9, and SKINTL. Conclusion: We have identified four QTLs with genome-wide significance and several promising candidates that could potentially be associated with ADHD (CXCR4, UPF1, SETD5, NALCN-AS1, ERC1, SOX2-OT, FGFR2, ANO4, and TBL1XR1). Further replication studies with larger sample sizes are needed.

Genome-wide study of copy number variation implicates multiple novel loci for schizophrenia risk in Han Chinese family trios

“…In a mice model, MLIP is co-expression with PDE11A, a gene involved in social deficits of disorders of adulthood (including SCZ) ( Hegde et al., 2016 ). Moreover, the SNP rs9464011 in the intron of MLIP was significantly associated with attention-deficit/hyperactivity disorder in a family-based genome-wide quantitative trait loci analysis in a Korean population ( Kweon et al., 2018 ). Our results support the well-known pleiotropy of CNVs and once again demonstrate that some risk loci are shared by different neuropsychiatric disorders.…”

Fibroblast growth factor receptor 2 (FGFR2), a new gene involved in the genesis of Autism Spectrum Disorder

“…Interestingly, these two chromosomes harbour important genes implicated in central nervous system development and body growth, including the FGFR2 gene. Lastly, Kweon et al (2018) carried out a genome-wide analysis on 135 ADHD subjects, revealing four quantitative trait loci comprising several promising candidates that could potentially be related to ADHD, inclusive of FGFR2. This is of interest if considered that our patient also received a co-diagnosis of ADHD (Table 1).…”

Discovery of eQTL Alleles Associated with Autism Spectrum Disorder: A Case–Control Study

“…One other example of an association with PsychENCODE can be found in the CIDEA gene, which was identified by our study and was shown to be significantly down-regulated in ASD-affected individuals by PsychENCODE. Additionally, CIDEA has shown to be down-regulated in obesity and associated with ADHD, both of which often appear in tandem with ASD (Cortese & Vincenzi, 2012 ; Croen et al, 2015 ; Kweon et al, 2018 ; Lee & Ousley, 2006 ; Nordström et al, 2005 ). In total, the eQTLs described here are evidence of tissue-specific regulation across both brain and non-brain tissues.…”