title: Genetic Risk Score Analysis in Early-Onset Bipolar Disorder.
abstract: In this study, we performed a candidate genetic risk score (GRS) analysis of early-onset bipolar disorder (BD).
  
  
  
  Treatment of Early Age Mania (TEAM) study enrollment and sample collection took place from 2003 to 2008. Mayo Clinic Bipolar Biobank samples were collected from 2009 to 2013. Genotyping and analyses for the present study took place from 2013 to 2014. The diagnosis of BD was based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. Eight single-nucleotide polymorphisms (SNPs), previously reported in genome-wide association studies to be associated with BD, were chosen for GRS analysis in early-onset bipolar disease. These SNPs map to 3 genes: CACNA1C (calcium channel, voltage-dependent, L type, alpha 1C subunit), ANK3 (ankyrin-3, node of Ranvier [ankyrin G]), and ODZ4 (teneurin transmembrane protein 4 [formerly "odz, odd Oz/10-m homolog 4 {Drosophila}, ODZ4"]). The 8 candidate SNPs were genotyped in patients from the TEAM study (n = 69); adult patients with BD (n = 732), including a subset with early-onset illness (n = 192); and healthy controls (n = 776). GRS analyses were performed to compare early-onset cases with controls. In addition, associations of early-onset BD with individual SNPs and haplotypes were explored.
  
  
  
  GRS analysis revealed associations of the risk score with early-onset BD (P = .01). Gene-level haplotype analysis comparing TEAM patients with controls suggested association of early-onset BD with a CACNA1C haplotype (global test, P = .01). At the level of individual SNPs, comparison of TEAM cases with healthy controls provided nominally significant evidence for association of SNP rs10848632 in CACNA1C with early-onset BD (P = .017), which did not remain significant after correction for multiple comparisons.
  
  
  
  These preliminary analyses suggest that previously identified BD risk loci, especially CACNA1C, have a role in early-onset BD, possibly with stronger effects than for late-onset BD.
authors.affiliation: Department of Psychiatry and Psychology, Mayo Clinic, 200 First St SW, Rochester, MN 55905. croarkin.paul@mayo.edu.|Departments of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Croarkin
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri, USA.
authors.forename: Joan L
authors.initials: JL
authors.lastname: Luby
authors.affiliation: Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Cercy
authors.affiliation: Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Geske
authors.affiliation: Departments of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Marin
authors.initials: M
authors.lastname: Veldic
authors.affiliation: Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Simonson
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Children's National Medical Center, Washington, DC, USA.
authors.forename: Paramjit T
authors.initials: PT
authors.lastname: Joshi
authors.affiliation: Department of Psychiatry and Behavioral Sciences, The University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Karen Dineen
authors.initials: KD
authors.lastname: Wagner
authors.affiliation: Department of Psychiatry, Weill Cornell Medical College, New York, New York, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Walkup
authors.affiliation: Departments of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Malik M
authors.initials: MM
authors.lastname: Nassan
authors.affiliation: Universidad Autonóma de Nuevo León, San Nicolás de los Garza, Mexico.
authors.forename: Alfredo B
authors.initials: AB
authors.lastname: Cuellar-Barboza
authors.affiliation: Lindner Center of HOPE, Mason, Ohio, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Casuto
authors.affiliation: Lindner Center of HOPE, Mason, Ohio, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: McElroy
authors.affiliation: The REACH Institute, New York, New York, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Jensen
authors.affiliation: Departments of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Frye
authors.affiliation: Departments of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota, USA.|Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Biernacka
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001714:Bipolar Disorder / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D060005:Genotyping Techniques; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D055815:Young Adult