title: Replicated association of Synaptotagmin (SYT1) with ADHD and its broader influence in externalizing behaviors.
abstract: Attention-Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric disorder, affecting both children and adults. The Soluble N-ethylmaleimide sensitive factor Attachment REceptors (SNARE) complex has been implicated in ADHD pathophysiology since it is a key component of neurotransmitter release events and neurodevelopment processes, and SNPs in this complex have been associated with ADHD. Here we aim to analyze the effects of SNARE complex variants on ADHD susceptibility and its clinical heterogeneity in affected adults. We tested the association between ADHD and polymorphisms on the SNARE genes STX1A (rs2228607), SYT1 (rs1880867 and rs2251214), VAMP2 (26bp Ins/Del) and SNAP25 (rs6108461 and rs8636) on a sample comprised of 548 adults with ADHD and 644 non-affected controls. Regarding clinical heterogeneity, we further investigated the effects of associated SNPs on age at onset of impairment due to ADHD and on relevant externalizing behaviors (i.e. school suspensions/expulsions and problems with law/authority) and comorbidities (i.e. Substance Use Disorder, Oppositional Defiant Disorder, Conduct Disorder and Antisocial Personality Disorder). We replicated a previously reported association between SYT1-rs2251214 and ADHD in adulthood. This SNP was also associated with age at onset of impairment due to ADHD symptoms and with a range of externalizing phenotypes. These findings involving SYT1 suggest that variation in neurotransmitter exocytosis mechanisms may represent an underlying genetic factor shared by a spectrum of externalizing behaviors and disorders, including - but not restricted to - ADHD.
authors.affiliation: Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Renata Basso
authors.initials: RB
authors.lastname: Cupertino
authors.affiliation: Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Jaqueline Bohrer
authors.initials: JB
authors.lastname: Schuch
authors.affiliation: Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Cibele Edom
authors.initials: CE
authors.lastname: Bandeira
authors.affiliation: Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Bruna Santos
authors.initials: BS
authors.lastname: da Silva
authors.affiliation: Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Diego Luiz
authors.initials: DL
authors.lastname: Rovaris
authors.affiliation: Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Djenifer B
authors.initials: DB
authors.lastname: Kappel
authors.affiliation: PPGBIOTEC - Postgraduate Program in Biotechnology, Centro Universitário Univates, Lajeado, Brazil.
authors.forename: Verônica
authors.initials: V
authors.lastname: Contini
authors.affiliation: Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Angélica
authors.initials: A
authors.lastname: Salatino-Oliveira
authors.affiliation: Department of Psychiatry, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Eduardo Schneider
authors.initials: ES
authors.lastname: Vitola
authors.affiliation: ADHD Outpatient Program, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
authors.forename: Rafael Gomes
authors.initials: RG
authors.lastname: Karam
authors.affiliation: Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; ADHD Outpatient Program, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
authors.forename: Mara Helena
authors.initials: MH
authors.lastname: Hutz
authors.affiliation: Department of Psychiatry, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; ADHD Outpatient Program, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil; National Institute of Developmental Psychiatry for Children and Adolescents, Brazil.
authors.forename: Luis Augusto
authors.initials: LA
authors.lastname: Rohde
authors.affiliation: Department of Psychiatry, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; ADHD Outpatient Program, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
authors.forename: Eugenio Horacio
authors.initials: EH
authors.lastname: Grevet
authors.affiliation: Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; ADHD Outpatient Program, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil. Electronic address: claiton.bau@ufrgs.br.
authors.forename: Claiton Henrique Dotto
authors.initials: CHD
authors.lastname: Bau
authors.affiliation: Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Nina Roth
authors.initials: NR
authors.lastname: Mota
mesh_terms: D000987:Antisocial Personality Disorder / Q000209:etiology; D001289:Attention Deficit Disorder with Hyperactivity / Q000150:complications* / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D019955:Conduct Disorder / Q000209:etiology; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000209:etiology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D050863:Synaptotagmin I / Q000235:genetics*
chemical_list: C494310:SYT1 protein, human; D050863:Synaptotagmin I
keywords: ASPD; Antisocial Personality Disorder; Attention-Deficit/Hyperactivity Disorder; Meta-analysis; SNARE; Synaptotagmin