T47. DISSECTING THE SHARED BIOLOGY BETWEEN ADHD AND MIGRAINE UTILIZING LOCAL GENETIC CORRELATION

• Published in: European neuropsychopharmacology 2023-10, Vol.75, p.S186-S187
• Main Authors: Rovaris, Diego Luiz, Ciochetti, Nicolas Pereira, Junger-Santos, Iago, Bandeira, Cibele Edom, Tavares, Maria Eduarda, Grevet, Eugênio Horacio, Bau, Claiton Henrique Dotto, da Silva, Bruna Santos
• Format: Article
• Language: English
• ISSN: 0924-977X; 1873-7862
• DOI: 10.1016/j.euroneuro.2023.08.332

Attention-deficit/hyperactivity disorder (ADHD) is a complex condition characterized by inattention, hyperactivity, or both symptoms. Among the various comorbidities associated with ADHD, migraines are particularly common and strongly linked to the disorder. The primary treatment for migraines typically involves the use of analgesics, such as paracetamol. However, it is important to note that epidemiological evidence has suggested a potential risk factor for ADHD in the offspring of pregnant women who use paracetamol. In this study, we aimed to enhance our understanding of the genetic relationships between ADHD, migraines, and paracetamol use. We utilized genome-wide association study (GWAS) summary statistics for ADHD, migraines, and paracetamol use (a proxy for headaches and pain). Initially, we employed LD Score Regression (LDSC) to estimate the global correlations between ADHD and migraines, as well as between ADHD and paracetamol use. Subsequently, we employed Local Analysis of [co]Variant Annotation (LAVA) to explore the bivariate local correlations between each pair of phenotypes, dividing the genome into 2,495 semi-independent LD blocks. We assessed loci with significant local h2SNP for both phenotypes to determine their bivariate local correlation. Moreover, we performed an enrichment analysis of genes associated with the regions identified through the local correlation analysis. Finally, we investigated whether these genes or their associated functions overlap with the pharmacokinetics or pharmacodynamics of paracetamol, aiming to shed light on potential mechanisms that underlie the observed association. Global genetic correlation among all three variables was positive and significant. The local analysis yielded four loci for both ADHD x migraines and ADHD x paracetamol (eight in total). They span chr 1, 3, 5, 6, 7, 14, and 19, but no region appeared in both. The enrichment analysis of the genes within these regions revealed functions ranging from voltage-gated potassium channel activity to phosphatidylcholine metabolism. There was no presence of paracetamol-metabolizing genes. Most importantly, it did not overlap with known paracetamol pathways. However, after a ``drug enrichment analysis'' that suggests other possible pathways affected by paracetamol, it overlapped with voltage-gated potassium channel activity (GO:0005249), associated with potassium channels present in chr. 1 (bp: 111134063-112489248) of the local analysis between ADHD and migr