title: LPHN3 and attention-deficit/hyperactivity disorder: a susceptibility and pharmacogenetic study.
abstract: Latrophilin 3 (LPHN3) is a brain-specific member of the G-protein coupled receptor family associated to both attention-deficit/hyperactivity disorder (ADHD) genetic susceptibility and methylphenidate (MPH) pharmacogenetics. Interactions of LPHN3 variants with variants harbored in the 11q chromosome improve the prediction of ADHD development and medication response. The aim of this study was to evaluate the role of LPHN3 variants in childhood ADHD susceptibility and treatment response in a naturalistic clinical cohort. The association between LPHN3 and ADHD was evaluated in 523 children and adolescents with ADHD and 132 controls. In the pharmacogenetic study, 172 children with ADHD were investigated. The primary outcome measure was the parent-rated Swanson, Nolan and Pelham Scale - version IV applied at baseline, first and third months of treatment with MPH. The results reported herein suggest the CGC haplotype derived from single nucleotide polymorphisms (SNPs) rs6813183, rs1355368 and rs734644 as an ADHD risk haplotype (P = 0.02, OR = 1.46). Although non-significant after multiple testing correction, its interaction with the 11q chromosome SNP rs965560 slightly increases risk (P = 0.03, OR = 1.55). Homozygous individuals for the CGC haplotype showed faster response to MPH treatment as a significant interaction effect between CGC haplotype and treatment over time was observed (P < 0.001). Homozygous individuals for the GT haplotype derived from SNPs rs6551665 and rs1947275 showed a nominally significant interaction with treatment over time (P = 0.04). Our findings replicate previous findings reporting that LPHN3 confers ADHD susceptibility, and moderates MPH treatment response in children and adolescents with ADHD.
authors.affiliation: Genetics Department, Federal University of Rio Grande do Sul, Porto Alegre, RS.
authors.forename: E M
authors.initials: EM
authors.lastname: Bruxel
authors.affiliation: Genetics Department, Federal University of Rio Grande do Sul, Porto Alegre, RS.
authors.forename: A
authors.initials: A
authors.lastname: Salatino-Oliveira
authors.affiliation: Genetics Department, Federal University of Rio Grande do Sul, Porto Alegre, RS.
authors.forename: G C
authors.initials: GC
authors.lastname: Akutagava-Martins
authors.affiliation: Genetics Department, Federal University of Rio Grande do Sul, Porto Alegre, RS.
authors.forename: L
authors.initials: L
authors.lastname: Tovo-Rodrigues
authors.affiliation: Genetics Department, Federal University of Rio Grande do Sul, Porto Alegre, RS.
authors.forename: J P
authors.initials: JP
authors.lastname: Genro
authors.affiliation: Division of Child and Adolescent Psychiatry, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, RS.
authors.forename: C P
authors.initials: CP
authors.lastname: Zeni
authors.affiliation: Institute for Developmental Psychiatry for Children and Adolescents, Porto Alegre, RS.|Department of Psychiatry, University of São Paulo Medical School, São Paulo, SP, Brazil.
authors.forename: G V
authors.initials: GV
authors.lastname: Polanczyk
authors.affiliation: Division of Child and Adolescent Psychiatry, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, RS.
authors.forename: R
authors.initials: R
authors.lastname: Chazan
authors.affiliation: Division of Child and Adolescent Psychiatry, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, RS.
authors.forename: M
authors.initials: M
authors.lastname: Schmitz
authors.affiliation: Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Arcos-Burgos
authors.affiliation: Division of Child and Adolescent Psychiatry, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, RS.|Institute for Developmental Psychiatry for Children and Adolescents, Porto Alegre, RS.
authors.forename: L A
authors.initials: LA
authors.lastname: Rohde
authors.affiliation: Genetics Department, Federal University of Rio Grande do Sul, Porto Alegre, RS.
authors.forename: M H
authors.initials: MH
authors.lastname: Hutz
mesh_terms: D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy / Q000235:genetics*; D016022:Case-Control Studies; D000697:Central Nervous System Stimulants / Q000627:therapeutic use*; D002648:Child; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008774:Methylphenidate / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D018000:Receptors, Peptide / Q000235:genetics*
chemical_list: C513284:ADGRL3 protein, human; D000697:Central Nervous System Stimulants; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D008774:Methylphenidate
keywords: Attention-deficit/hyperactivity disorder; LPHN3; genetic susceptibility; medication response; pharmacogenetics