Genetic risk score analysis in early-onset bipolar disorder

Paul E. Croarkin, Joan L. Luby, Kelly Cercy, Jennifer R. Geske, Marin Veldic, Matthew Simonson, Paramjit T. Joshi, Karen Wagner, John T. Walkup, Malik M. Nassan, Alfredo B. Cuellar-Barboza, Leah Casuto, Susan L. McElroy, Peter S. Jensen, Mark A. Frye, Joanna M. Biernacka

Research output: Contribution to journalArticle

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Abstract

Objective: In this study, we performed a candidate genetic risk score (GRS) analysis of early-onset bipolar disorder (BD). Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)1337-1343
Number of pages7
JournalJournal of Clinical Psychiatry
Volume78
Issue number9
DOIs
StatePublished - Nov 1 2017

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Bipolar Disorder
Single Nucleotide Polymorphism
Ankyrins
Haplotypes
Ranvier's Nodes
L-Type Calcium Channels
Genome-Wide Association Study
Therapeutics
Diagnostic and Statistical Manual of Mental Disorders
Genes
Drosophila

ASJC Scopus subject areas

  • Psychiatry and Mental health

Cite this

Croarkin, P. E., Luby, J. L., Cercy, K., Geske, J. R., Veldic, M., Simonson, M., ... Biernacka, J. M. (2017). Genetic risk score analysis in early-onset bipolar disorder. Journal of Clinical Psychiatry, 78(9), 1337-1343. https://doi.org/10.4088/JCP.15m10314

Genetic risk score analysis in early-onset bipolar disorder. / Croarkin, Paul E.; Luby, Joan L.; Cercy, Kelly; Geske, Jennifer R.; Veldic, Marin; Simonson, Matthew; Joshi, Paramjit T.; Wagner, Karen; Walkup, John T.; Nassan, Malik M.; Cuellar-Barboza, Alfredo B.; Casuto, Leah; McElroy, Susan L.; Jensen, Peter S.; Frye, Mark A.; Biernacka, Joanna M.

In: Journal of Clinical Psychiatry, Vol. 78, No. 9, 01.11.2017, p. 1337-1343.

Research output: Contribution to journalArticle

Croarkin, PE, Luby, JL, Cercy, K, Geske, JR, Veldic, M, Simonson, M, Joshi, PT, Wagner, K, Walkup, JT, Nassan, MM, Cuellar-Barboza, AB, Casuto, L, McElroy, SL, Jensen, PS, Frye, MA & Biernacka, JM 2017, 'Genetic risk score analysis in early-onset bipolar disorder', Journal of Clinical Psychiatry, vol. 78, no. 9, pp. 1337-1343. https://doi.org/10.4088/JCP.15m10314
Croarkin PE, Luby JL, Cercy K, Geske JR, Veldic M, Simonson M et al. Genetic risk score analysis in early-onset bipolar disorder. Journal of Clinical Psychiatry. 2017 Nov 1;78(9):1337-1343. https://doi.org/10.4088/JCP.15m10314
Croarkin, Paul E. ; Luby, Joan L. ; Cercy, Kelly ; Geske, Jennifer R. ; Veldic, Marin ; Simonson, Matthew ; Joshi, Paramjit T. ; Wagner, Karen ; Walkup, John T. ; Nassan, Malik M. ; Cuellar-Barboza, Alfredo B. ; Casuto, Leah ; McElroy, Susan L. ; Jensen, Peter S. ; Frye, Mark A. ; Biernacka, Joanna M. / Genetic risk score analysis in early-onset bipolar disorder. In: Journal of Clinical Psychiatry. 2017 ; Vol. 78, No. 9. pp. 1337-1343.
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abstract = "Objective: In this study, we performed a candidate genetic risk score (GRS) analysis of early-onset bipolar disorder (BD). Methods: 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. Results: 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. Conclusions: 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.",
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T1 - Genetic risk score analysis in early-onset bipolar disorder

AU - Croarkin, Paul E.

AU - Luby, Joan L.

AU - Cercy, Kelly

AU - Geske, Jennifer R.

AU - Veldic, Marin

AU - Simonson, Matthew

AU - Joshi, Paramjit T.

AU - Wagner, Karen

AU - Walkup, John T.

AU - Nassan, Malik M.

AU - Cuellar-Barboza, Alfredo B.

AU - Casuto, Leah

AU - McElroy, Susan L.

AU - Jensen, Peter S.

AU - Frye, Mark A.

AU - Biernacka, Joanna M.

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N2 - Objective: In this study, we performed a candidate genetic risk score (GRS) analysis of early-onset bipolar disorder (BD). Methods: 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. Results: 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. Conclusions: 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.

AB - Objective: In this study, we performed a candidate genetic risk score (GRS) analysis of early-onset bipolar disorder (BD). Methods: 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. Results: 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. Conclusions: 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.

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