Genetic Correlation Analysis and Transcriptome-wide Association Study Suggest the Overlapped Genetic Mechanism between Gout and Attention-deficit Hyperactivity Disorder

Abstract

Objectives: Gout is a common inflammatory arthritis, which is caused by hyperuricemia. Limited efforts have been paid to systematically explore the relationships between gout and common psychiatric disorders. Methods: Genome-wide association study summary data of gout were obtained from the GeneATLAS, which contained 452,264 participants including 3,528 gout cases. Linkage disequilibrium score regression (LDSC) was first conducted to evaluate the genetic relationships between gout and 5 common psychiatric disorders. Transcriptome-wide association studies (TWAS) was then conducted to explore the potential biological mechanism underlying the observed genetic correlation between gout and attention-deficit hyperactivity disorder (ADHD). The Database for Annotation, Visualization and Integrated Discovery online functional annotation system was applied for pathway enrichment analysis and gene ontology enrichment analysis. Results: LDSC analysis observed significant genetic correlation between gout and ADHD (genetic correlation coefficients = 0.29, standard error = 0.09 and P value = 0.0015). Further TWAS of gout identified 105 genes with P value < 0.05 in muscle skeleton and 228 genes with P value < 0.05 in blood. TWAS of ADHD also detected 300 genes with P value < 0.05 in blood. Further comparing the TWAS results identified 9 common candidate genes shared by gout and ADHD, such as CD300C ( P gout = 0.0040; P ADHD = 0.0226), KDM6B ( P gout = 0.0074; P ADHD = 0.0460), and BST1 ( P gout = 0.0349; P ADHD = 0.03560). Conclusion: We observed genetic correlation between gout and ADHD and identified multiple candidate genes for gout and ADHD.

A scoping review and comparison of approaches for measuring genetic heterogeneity in psychiatric disorders

“…et al, 2018aDuncan L.E. et al, , 2018bFrei et al, 2019;Gibson et al, 2017;Grotzinger et al, 2019;Hammerschlag et al, 2017;Hill et al, 2016;Hofer et al, 2020;Hubbard et al, 2016;Hübel et al, 2019;Ikeda et al, 2019;Masashi Ikeda et al, 2018;Jang et al, 2020;Jansen et al, 2019;Kafle et al, 2020;Khramtsova et al, 2019;Lam et al, 2019;Lane et al, 2017;Lee et al, 2019;Levey et al, 2020;Li et al, 2021;Lind et al, 2020;Lo et al, 2017; Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium (Corporate Collaborator) et al, 2015;Marees et al, 2021Marees et al, , 2020Meier et al, 2019;Meng et al, 2020;Milaneschi et al, 2017;Mullins et al, 2021;Ni et al, 2019;Nudel et al, 2019;Ohi et al, 2020aOhi et al, , 2020bPasman et al, 2018;Peterson et al, 2018;Polimanti et al, 2018;Purves et al, 2020;Roelfs et al, 2021;Ruderfer et al, 2020;Savage et al, 2018;…”

“…Eighty-seven studies quantified genetic correlation (Abdellaoui et al, 2021, 2019; Adams et al , 2020; Amare et al , 2020; Andersson et al , 2020; Anttila et al , 2018; Bahrami et al , 2020; Barkhuizen et al , 2020; Brick et al , 2019; Cabana-Domínguez et al , 2019; Campbell et al , 2021; Charney et al , 2017; Cheng et al , 2020; Clifton et al , 2018; Coleman et al , 2020; Coombes et al , 2020; Cross-Disorder Group of the Psychiatric Genomics Consortium, 2013; Direk et al , 2017; Duncan et al , 2017; Duncan L.E. et al ., 2018a, 2018b; Frei et al , 2019; Gibson et al , 2017; Grotzinger et al , 2019; Hammerschlag et al , 2017; Hill et al , 2016; Hofer et al , 2020; Hubbard et al , 2016; Hübel et al , 2019; Ikeda et al , 2019; Masashi Ikeda et al , 2018; M. Ikeda et al , 2018; Jang et al , 2020; Jansen et al , 2019; Kafle et al , 2020; Khramtsova et al , 2019; Lam et al , 2019; Lane et al , 2017; Lee et al , 2019; Levey et al , 2020; Li et al , 2021; Lind et al , 2020; Lo et al , 2017; Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium (Corporate Collaborator) et al ., 2015; Marees et al, 2021, 2020; Meier et al , 2019; Meng et al , 2020; Milaneschi et al , 2017; Mullins et al , 2021; Ni et al , 2019; Nudel et al , 2019; Ohi et al, 2020a, 2020b; Pasman et al , 2018; Peterson et al , 2018; Polimanti et al , 2018; Purves et al , 2020; Roelfs et al , 2021; Ruderfer et al , 2020; Savage et al , 2018; Selzam et al , 2018; Shadrin et al , 2018; Sheerin et al , 2020; Smit et al , 2020; Smith et al , 2016; Solberg et al , 2019; Stein et al , 2016; Stergiakouli et al , 2017; Strawbridge et...…”

The Prevalence of Hyperuricemia and the Association Between Hyperuricemia and Age in Patients with Psychiatric Disorders to a General Hospital: A Cross-Section Study

“… 42 There is evidence of a significant relationship between SUA and attention-deficit hyperactivity disorder at the genetic level. 43 …”

Common Genetic Risk Factors in ASD and ADHD Co-occurring Families

“…Notably, both top candidate genes in the two linkage regions ( KDM6B, KMT2D ) are involved in the histone lysine methylation process. Histone modification is a central process regulating gene expression during neurodevelopment and mutations in KDM6B have been linked to multiple NDDs (47), including ADHD (48, 49). At the whole genome level, 31 of the high-confidence candidate genes were identified in previous studies or NDD gene databases.…”

“…The KDM6B protein demethylates trimethylated lysine-27 on histone H3. Pathogenic alterations in histone lysine methylation and demethylation genes have been associated with multiple NDDs (47), including ADHD (48,49). KDM6B is also annotated in NDD databases such as SFARI and iPSYCH, and it is identified as one of the 102 risk genes in a recent large ASD study (50).…”