Genetics and epigenetics of attention-deficit/hyperactivity disorder and comorbid conditions
- Autores: Anu Shivalikanjli
- Directores de la Tesis: Bru Cormand Rifa (dir. tes.), Stephen V. Faraone (codir. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2021
- Idioma: inglés
- Tribunal Calificador de la Tesis: Daniel Grinberg Vaisman (presid.), Silvia Alemany Sierra (secret.), Gerard Muntané Medina (voc.)
- Programa de doctorado: Programa de Doctorado en Genética por la Universidad de Barcelona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TESEO
- Resumen
The broad objectives of this work are the identification of genes that contribute to the susceptibility to attention-deficit/hyperactivity disorder (ADHD) and cocaine dependence, two disorders that co-occur in patients. In this Thesis, we describe (i) the contribution to ADHD of allele-specific methylation (ASM), an epigenetic mechanism that involves single single- nucleotide polymorphisms (SNPs) correlating with differential levels of DNA methylation at CpG sites, (ii) the role of microRNA (miRNA) genes in ADHD, and (iii) a genome-wide association meta-analysis of cocaine dependence. We also explore the common genetic basis that explains the comorbidity between these disorders. The main results from the three studies include: (i) Common genetic risk variants for ADHD identified in a previous genome-wide association study (GWAS) that included 20,000 cases and 35,000 controls are enriched in SNPs that correlate with levels of DNA methylation. Eight ASM SNPs were found significantly associated with ADHD and correlated with differential methylation at six CpG sites in cis in different brain areas. These six CpG sites are located at possible promoter regions of six genes expressed in brain: ARTN, C2orf82, NEUROD6, PIDD1, RPLP2 and GAL. Based on the bioinformatic functional analyses of these genes, our study highlights the candidacy of ARTN, C2orf82 and PIDD1 genes as potential contributors to ADHD susceptibility. (ii) We conducted a case-control association study to investigate the contribution to ADHD of common genetic variation in 1,761 autosomal miRNAs using pre-existing GWAS data from 20,000 cases and 35,000 controls. We identified significant associations of SNPs with ADHD that highlight 12 miRNA genes, all located within protein-coding genes. The associated variants are located in the putative regulatory regions of the miRNA genes or in the promoter region of the host protein-coding gene. We inspected the target genes, brain expression, homologs for the miRNAs and we propose miR-7-1 and miR-3666 as promising candidates since both are brain expressed, have validated brain-expressed targets, and homologs in model species. Pathway analysis of ADHD-associated miRNAs revealed miRNA-mediated regulation of serotonin receptor genes, well-known contributors to neurological functions and diseases. (iii) We performed the largest cocaine dependence GWAS meta-analysis in individuals of European ancestry, including 2,100 cases and 4,300 controls. Although SNP-based analysis revealed no genome-wide significant associations with cocaine dependence, probably due to limited sample size, gene-based analysis identified the HIST1H2BD gene, previously associated with schizophrenia. The estimated SNP-based heritability of cocaine dependence was estimated as 30%. A significant genetic correlation was found between cocaine dependence and ADHD, schizophrenia, major depressive disorder and risk-taking behaviour, suggesting a shared genetic basis across pathologies and traits. Polygenic risk score (PRS) analysis shows that all the comorbid features analysed (ADHD, schizophrenia, major depressive disorder, aggressiveness, antisocial personality or risk-taking behaviour) can predict cocaine dependence. Overall, we identified common genetic and epigenetic risk factors that underlie the susceptibility to ADHD and to cocaine dependence. The results reinforce the idea that epigenetic mechanisms dictate the differential expression of genes that may be causal to ADHD. Cocaine dependence, which has been widely believed to occur under environmental and epigenetic influences, is also in part genetically determined. Finally, ADHD and cocaine dependence are comorbid disorders, and the observed genetic correlation between these conditions can reflect biological pleiotropy.
