Moreno Alcázar, AnaRamos Quiroga, Josep AntoniRibasés, MartaSánchez-Mora, CristinaPalomar, GloriaBosch, RosaSalavert, JosepFortea, LydiaMonté-Rubio, Gemma C.Canales-Rodrıguez, Erick J.Milham, Michael P.Castellanos, Francisco X.Casas, MiguelPomarol-Clotet, EdithRadua, Joaquim2021-07-122021-07-122021Moreno-Alcázar A, Ramos-Quiroga JA, Ribases M, Sánchez-Mora C, Palomar G, Bosch R, Salavert J, Fortea L, Monté-Rubio GC, Canales-Rodríguez EJ, Milham MP, Castellanos FX, Casas M, Pomarol-Clotet E, Radua J. Brain structural and functional substrates of ADGRL3 (latrophilin 3) haplotype in attention-deficit/hyperactivity disorder. Sci Rep. 2021;11(1):2373. DOI: 10.1038/s41598-021-81915-z2045-2322http://hdl.handle.net/10230/48154Previous studies have shown that the gene encoding the adhesion G protein-coupled receptor L3 (ADGRL3; formerly latrophilin 3, LPHN3) is associated with Attention-Deficit/Hyperactivity Disorder (ADHD). Conversely, no studies have investigated the anatomical or functional brain substrates of ADGRL3 risk variants. We examined here whether individuals with different ADGRL3 haplotypes, including both patients with ADHD and healthy controls, showed differences in brain anatomy and function. We recruited and genotyped adult patients with combined type ADHD and healthy controls to achieve a sample balanced for age, sex, premorbid IQ, and three ADGRL3 haplotype groups (risk, protective, and others). The final sample (n = 128) underwent structural and functional brain imaging (voxel-based morphometry and n-back working memory fMRI). We analyzed the brain structural and functional effects of ADHD, haplotypes, and their interaction, covarying for age, sex, and medication. Individuals (patients or controls) with the protective haplotype showed strong, widespread hypo-activation in the frontal cortex extending to inferior temporal and fusiform gyri. Individuals (patients or controls) with the risk haplotype also showed hypo-activation, more focused in the right temporal cortex. Patients showed parietal hyper-activation. Disorder-haplotype interactions, as well as structural findings, were not statistically significant. To sum up, both protective and risk ADGRL3 haplotypes are associated with substantial brain hypo-activation during working memory tasks, stressing this gene's relevance in cognitive brain function. Conversely, we did not find brain effects of the interactions between adult ADHD and ADGRL3 haplotypes.application/pdfeng© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41598-021-81915-zADHDFunctional magnetic resonance imagingGenotyping and haplotypingMagnetic resonance imaginginfo:eu-repo/semantics/openAccess