A genome wide association study suggests the association of muskelin with early onset bipolar disorder: Implications for a GABAergic epileptogenic neurogenesis model

Malik Nassan, Qingqin Li, Paul E Croarkin, Wenan Chen, Colin L. Colby, Marin D Veldic, Susan L. McElroy, Gregory D. Jenkins, Euijung Ryu, Julie M Cunningham, Marion Leboyer, Mark A Frye, Joanna M Biernacka

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Abstract

Background 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. Methods 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. Results 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. Limitations The sample sizes of the early-onset BD subgroups were relatively small. Conclusions 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.

Original languageEnglish (US)
Pages (from-to)120-129
Number of pages10
JournalJournal of Affective Disorders
Volume208
DOIs
StatePublished - Jan 15 2017

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Genome-Wide Association Study
Neurogenesis
Bipolar Disorder
Single Nucleotide Polymorphism
GABA-A Receptors
Synaptic Transmission
Neuronal Plasticity
Age of Onset
Anticonvulsants
Sample Size
gamma-Aminobutyric Acid
Genes
Meta-Analysis
Hippocampus
Alleles
Genome
Gene Expression
Neurons

ASJC Scopus subject areas

  • Clinical Psychology
  • Psychiatry and Mental health

Cite this

A genome wide association study suggests the association of muskelin with early onset bipolar disorder : Implications for a GABAergic epileptogenic neurogenesis model. / Nassan, Malik; Li, Qingqin; Croarkin, Paul E; Chen, Wenan; Colby, Colin L.; Veldic, Marin D; McElroy, Susan L.; Jenkins, Gregory D.; Ryu, Euijung; Cunningham, Julie M; Leboyer, Marion; Frye, Mark A; Biernacka, Joanna M.

In: Journal of Affective Disorders, Vol. 208, 15.01.2017, p. 120-129.

Research output: Contribution to journalArticle

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title = "A genome wide association study suggests the association of muskelin with early onset bipolar disorder: Implications for a GABAergic epileptogenic neurogenesis model",
abstract = "Background 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. Methods 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. Results 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. Limitations The sample sizes of the early-onset BD subgroups were relatively small. Conclusions 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.",
author = "Malik Nassan and Qingqin Li and Croarkin, {Paul E} and Wenan Chen and Colby, {Colin L.} and Veldic, {Marin D} and McElroy, {Susan L.} and Jenkins, {Gregory D.} and Euijung Ryu and Cunningham, {Julie M} and Marion Leboyer and Frye, {Mark A} and Biernacka, {Joanna M}",
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T1 - A genome wide association study suggests the association of muskelin with early onset bipolar disorder

T2 - Implications for a GABAergic epileptogenic neurogenesis model

AU - Nassan, Malik

AU - Li, Qingqin

AU - Croarkin, Paul E

AU - Chen, Wenan

AU - Colby, Colin L.

AU - Veldic, Marin D

AU - McElroy, Susan L.

AU - Jenkins, Gregory D.

AU - Ryu, Euijung

AU - Cunningham, Julie M

AU - Leboyer, Marion

AU - Frye, Mark A

AU - Biernacka, Joanna M

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N2 - Background 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. Methods 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. Results 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. Limitations The sample sizes of the early-onset BD subgroups were relatively small. Conclusions 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.

AB - Background 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. Methods 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. Results 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. Limitations The sample sizes of the early-onset BD subgroups were relatively small. Conclusions 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.

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