title: A genome wide association study suggests the association of muskelin with early onset bipolar disorder: Implications for a GABAergic epileptogenic neurogenesis model.
abstract: Although multiple genes have been implicated in bipolar disorder (BD), they explain only a small proportion of its heritability. Identifying additional BD risk variants may be impaired by phenotypic heterogeneity, which is usually not taken into account in genome-wide association studies (GWAS). BD with early age at onset is a more homogeneous familial form of the disorder associated with greater symptom severity.
  
  
  
  We conducted a GWAS of early-onset BD (onset of mania/hypomania ≤19 years old) in a discovery sample of 419 cases and 1034 controls and a replication sample of 181 cases and 777 controls. These two samples were meta-analyzed, followed by replication of one signal in a third independent sample of 141 cases and 746 controls.
  
  
  
  No single nucleotide polymorphism (SNP) associations were genome-wide significant in the discovery sample. Of the top 15 SNPs in the discovery analysis, rs114034759 in the muskelin (MKLN1) gene was nominally significant in the replication analysis, and was among the top associations in the meta-analysis (p=2.63E-06, OR=1.9). In the third sample, this SNP was again associated with early-onset BD (p=0.036, OR=1.6). Gene expression analysis showed that the rs114034759 risk allele is associated with decreased hippocampal MKLN1 expression.
  
  
  
  The sample sizes of the early-onset BD subgroups were relatively small.
  
  
  
  Our results suggest MKLN1 is associated with early-onset BD. MKLN1 regulates cellular trafficking of GABA-A receptors, which is involved in synaptic transmission and plasticity, and is implicated in the mechanism of action of a group of antiepileptic mood stabilizers. These results therefore indicate that GABAergic neurotransmission may be implicated in early-onset BD. We propose that an increase in GABA-A receptors in the hippocampus in BD patients due to lower MKLN1 expression might increase the excitability during the GABA-excited early phase of young neurons, leading to an increased risk of developing a manic/hypomanic episode. Further studies are needed to test this model.
authors: Department of Psychiatry & Psychology, Mayo Clinic Depression Center, Mayo Clinic, Rochester, MN, United States. Electronic address: Nassan.Malik@mayo.edu.
authors: Malik
authors: M
authors: Nassan
authors: Janssen Research & Development, LLC, Titusville, NJ, United States.
authors: Qingqin
authors: Q
authors: Li
authors: Department of Psychiatry & Psychology, Mayo Clinic Depression Center, Mayo Clinic, Rochester, MN, United States.
authors: Paul E
authors: PE
authors: Croarkin
authors: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States.
authors: Wenan
authors: W
authors: Chen
authors: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States.
authors: Colin L
authors: CL
authors: Colby
authors: Department of Psychiatry & Psychology, Mayo Clinic Depression Center, Mayo Clinic, Rochester, MN, United States.
authors: Marin
authors: M
authors: Veldic
authors: Lindner Center of HOPE, Mason, OH and Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, United States.
authors: Susan L
authors: SL
authors: McElroy
authors: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States.
authors: Gregory D
authors: GD
authors: Jenkins
authors: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States.
authors: Euijung
authors: E
authors: Ryu
authors: Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States.
authors: Julie M
authors: JM
authors: Cunningham
authors: Université Paris-Est Créteil Val de Marne, Créteil, France.
authors: Marion
authors: M
authors: Leboyer
authors: Department of Psychiatry & Psychology, Mayo Clinic Depression Center, Mayo Clinic, Rochester, MN, United States.
authors: Mark A
authors: MA
authors: Frye
authors: Department of Psychiatry & Psychology, Mayo Clinic Depression Center, Mayo Clinic, Rochester, MN, United States; Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States. Electronic address: Biernacka.Joanna@mayo.edu.
authors: Joanna M
authors: JM
authors: Biernacka
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D001714:Bipolar Disorder / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008957:Models, Genetic; D055495:Neurogenesis / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011963:Receptors, GABA-A / Q000378:metabolism; D055815:Young Adult
chemical_list: D015815:Cell Adhesion Molecules; D005819:Genetic Markers; D047908:Intracellular Signaling Peptides and Proteins; C503019:MKLN1 protein, human; D011963:Receptors, GABA-A