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 Dineen 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

doi:10.4088/JCP.15m10314

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 Dineen 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 journal › Article › peer-review

12 Scopus citations

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 language	English (US)
Pages (from-to)	1337-1343
Number of pages	7
Journal	Journal of Clinical Psychiatry
Volume	78
Issue number	9
DOIs	https://doi.org/10.4088/JCP.15m10314
State	Published - Nov 1 2017

ASJC Scopus subject areas

Psychiatry and Mental health

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10.4088/JCP.15m10314

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Croarkin, P. E., Luby, J. L., Cercy, K., Geske, J. R., Veldic, M., Simonson, M., Joshi, P. T., Wagner, K. D., Walkup, J. T., Nassan, M. M., Cuellar-Barboza, A. B., Casuto, L., McElroy, S. L., Jensen, P. S., Frye, M. A., & 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

@article{db5de6fa164b4805b2e63be321e48cc7,

title = "Genetic risk score analysis in early-onset bipolar disorder",

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.",

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

note = "Funding Information: age mania.19 Patients in the adult EOC were also rigorously Brain and Behavior Research Foundation, and the Mayo Foundation and characterized on the basis of a review of SCID and EHR data, andAssureRxHealth.DrLubyhas received grant or research support from has received in-kind support for equipment and supplies from Neuronetics with independent confirmation by 2 child and adolescent NIMH, the Communities Healing Adolescent Depression and Suicide (CHADS) psychiatrists. These factors are critical, given the heterogeneity Coalition, and the Sydney R. Baer Jr Foundation and has received royalties from of BD and of early-onset mood disorders in general. has received honoraria from UBM Medica, American Psychiatric Association, Guilford Press. DrSimonsonis currently employed by Sqrrl Data. DrWagner However, it is important to note the limitations of this Las Vegas Psychiatric Society, American Academy of Child and Adolescent exploratory work. First, the sample size was small and the University Press, University of California San Diego, Baylor College of Medicine, Psychiatry,PartnersHealthcare,DoctorsHospitalatRenaissance,Oxford TEAM sample was particularly small, limiting the power of Weill Cornell Medical School, and Nevada Psychiatric Association. DrWalkup the study. Although no statistically significant associations has received free medication/placebo from the following pharmaceutical were observed for individual SNPs (after correction for (2007); was paid for a 1-time consultation with Shire (2011); is a paid speaker companies for NIMH-funded studies: Eli Lilly (2003), Abbott (2005), and Pfizer multiple testing), the OR estimates, particularly in the for the Tourette Syndrome National Education and Outreach Program of the comparisons of early-onset BD cases with controls, indicated Centers for Disease Control and Prevention; receives grant funding from The National Center on Birth Defects and Developmental Disabilities at the US the same direction of effect as in the original reports of Hartwell Foundation and the Tourette Syndrome Association; receives royalties association with BD.12,15 Thus, low study power most likely Press, the American Academy of Child and Adolescent Psychiatry, and the for books on Tourette syndrome from Guilford Press and Oxford University had a role in the failure to identify significant associations at American Psychiatric Association; and is an unpaid adviser to the Anxiety and the SNP level. Second, the analyses were restricted to patients Depression Association of America, Consumer Reports, and the Trichotillomania of European ancestry, which limits the generalizability of our College of Medicine and the University of Cincinnati Health Physicians/UC LearningCenter.DrCasutois employed by the University of Cincinnati results; however, this approach has the important advantage Health at the Lindner Center of HOPE and is presently, or has been in the past of reducing the likelihood of confounding by population Laboratories, the Marriott Foundation, Naurex, Shire, and Takeda. DrMcElroyyear, a coinvestigator on research studies sponsored by Cephalon, Forest structure. Reliance on self-reported race/ethnicity is also a is employed by the University of Cincinnati College of Medicine, University of limitation, in that we cannot exclude the possibility of residual Cincinnati Health Physicians/UC Health, and the Lindner Center of HOPE; is a population stratification. Because genome-wide SNP data Bracket, F. Hoffmann-La Roche, MedAvante, Naurex, Novo Nordisk, Shire, and consultant to, or a member ofthe scientific advisory boards of, in the past year, were not available for these samples, more robust methods Sunovion; is presently, or has been in the past year, a principal investigator or such as principal components could not be applied to control Research and Quality in the US Department of Health and Human Services, a coinvestigator on research studies sponsored by the Agency for Healthcare for population stratification. Nevertheless, prior research Alkermes PLC, Cephalon Inc, Forest Laboratories Inc, the Marriott Foundation, has shown that self-reported ancestry is usually a reliable NIMH, Naurex, Orexigen Therapeutics, Shire, and Takeda; and is also an inventor approach for accounting for population structure in candidate Control Disorders and, along with the patent{\textquoteright}s assignee, University of Cincinnati, on US Patent No. 6,323,236 B2, Use of Sulfamate Derivatives for Treating Impulse gene studies.50 Third, in most cases, the classification of Cincinnati, Ohio, and has received payments from Johnson & Johnson adult samples as early-onset vs late-onset BD was based on patent.DrJensenis employed by the REACH Institute, New York, New York, and Pharmaceutical Research & Development, which has exclusive rights under the a retrospective review of records and patient report, which in the past 12 months has received charitable gift support from Shire and grant may have been biased or inexact. Also, it was not possible Foundation; is a part owner ofthe psychiatric consulting organization CATCH support from the Marriott Foundation and the Klingenstein Third Generation to characterize numerous, potentially important factors such Services Inc, New York City, New York; and receives book royalties from as co-occurring disorders, treatment history, and functional AmericanPsychiatricPublishing,CivicResearchInstituteInc,BallantineBooks, impairment. Finally, this study was limited to a small number Myriad, Pfizer, NIMH (R01 MH079261), the National Institute on Alcohol Abuse and Guilford Press. DrFrye has received grant support from AssureRx Health, of SNPs. It was not meant to fully characterize the genetics and Alcoholism (P20AA017830) in the National Institutes of Health at the US of early-onset BD; rather, we aimed to explore whether a consultant to Janssen Global Services, Mitsubishi Tanabe, Myriad Genetics, Department of Health and Human Services, and the Mayo Foundation; has been previously identified risk loci might have a more prominent Sunovion, and Teva; has received continuing medical education/travel/ role in early-onset illness. Other important limitations include presentation support from CME Outfitters and Sunovion. Dr Biernacka has the potential differences in comorbidity among cohorts. We on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism in received research funding as a principal investigator from the National Institute were unable to fully characterize and control for comorbidities the National Institutes of Health at the US Department of Health and Human in the present study because of differences between the case Medical Sciences in the National Institutes of Health at the US Department of Services; as a coinvestigator from NIMH and the National Institute of General groups and data collection methods. This may explain the Health and Human Services; and as a co-principal investigator from the Marriott lack of specificity among some of our findings. Finally, as we Foundation for the Mayo Clinic Bipolar Disorder Biobank. DrsVeldic, Joshi, discussed above, the poor longitudinal diagnostic stability other relationship relevant to the subject ofthis article.Nassan, and Cuellar-Barbozaand MssCercyand Geskereport no financial or of BD in childhood presents inherent limitations in the Funding/support:This study was funded by the Marriott Foundation and Mayo interpretation of our findings. Clinic Center for Individualized Medicine. The original TEAM study described In conclusion, this study used GRS analysis to demonstrate MH064846, U01 MH064850, U01 MH064851, U01 MH064868, U01 MH064869, in this manuscript received funding from NIMH cooperative grants U01 that the selected candidate loci contribute primarily to the U01 MH064887, U01 MH064911, and R01 MH051481. Dr Croarkin is supported by risk of early-onset BD rather than to the risk of late-onset NIMHunderAwardNumberK23MH100266. BD. Our results also suggested an association of early-onset Clinic Center for Individualized Medicine, and NIMH) had no role in the study Roleofthesponsor:Thefundingorganizations(MarriottFoundation,Mayo BD with a CACNA1C haplotype. Future studies with larger, design, data collection, analysis, interpretation of results, writing of the report, ethnically diverse samples and more detailed phenotypic orsubmissionofthemanuscript. characterizations will refine the understanding of genetic risk Mental Health, was not involved in the editorial review or decision to publish Disclaimer:Dr Wagner, Section Editor for Focus on Childhood and Adolescent profiles in early-onset BD. this article. The content of this report is solely the responsibility of the authors Funding Information: This study was funded by the Marriott Foundation and Mayo Clinic Center for Individualized Medicine. The original TEAM study described in this manuscript received funding from NIMH cooperative grants U01 MH064846, U01 MH064850, U01 MH064851, U01 MH064868, U01 MH064869, U01 MH064887, U01 MH064911, and R01 MH051481. Dr Croarkin is supported by NIMH under Award Number K23MH100266. Funding Information: bipolar I disorder were rigorously characterized by child and Online first:February 14, 2017. adolescent psychiatrists with a high level of expertise in early-Pfizer, the National Institute of Mental Health (NIMH) (K23 MH100266), the Potential conflicts of interest: DrCroarkinhas received grant support from Publisher Copyright: {\textcopyright} Copyright 2017 Physicians Postgraduate Press, Inc.",

year = "2017",

month = nov,

day = "1",

doi = "10.4088/JCP.15m10314",

language = "English (US)",

volume = "78",

pages = "1337--1343",

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TY - JOUR

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 Dineen

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.

N1 - Funding Information: age mania.19 Patients in the adult EOC were also rigorously Brain and Behavior Research Foundation, and the Mayo Foundation and characterized on the basis of a review of SCID and EHR data, andAssureRxHealth.DrLubyhas received grant or research support from has received in-kind support for equipment and supplies from Neuronetics with independent confirmation by 2 child and adolescent NIMH, the Communities Healing Adolescent Depression and Suicide (CHADS) psychiatrists. These factors are critical, given the heterogeneity Coalition, and the Sydney R. Baer Jr Foundation and has received royalties from of BD and of early-onset mood disorders in general. has received honoraria from UBM Medica, American Psychiatric Association, Guilford Press. DrSimonsonis currently employed by Sqrrl Data. DrWagner However, it is important to note the limitations of this Las Vegas Psychiatric Society, American Academy of Child and Adolescent exploratory work. First, the sample size was small and the University Press, University of California San Diego, Baylor College of Medicine, Psychiatry,PartnersHealthcare,DoctorsHospitalatRenaissance,Oxford TEAM sample was particularly small, limiting the power of Weill Cornell Medical School, and Nevada Psychiatric Association. DrWalkup the study. Although no statistically significant associations has received free medication/placebo from the following pharmaceutical were observed for individual SNPs (after correction for (2007); was paid for a 1-time consultation with Shire (2011); is a paid speaker companies for NIMH-funded studies: Eli Lilly (2003), Abbott (2005), and Pfizer multiple testing), the OR estimates, particularly in the for the Tourette Syndrome National Education and Outreach Program of the comparisons of early-onset BD cases with controls, indicated Centers for Disease Control and Prevention; receives grant funding from The National Center on Birth Defects and Developmental Disabilities at the US the same direction of effect as in the original reports of Hartwell Foundation and the Tourette Syndrome Association; receives royalties association with BD.12,15 Thus, low study power most likely Press, the American Academy of Child and Adolescent Psychiatry, and the for books on Tourette syndrome from Guilford Press and Oxford University had a role in the failure to identify significant associations at American Psychiatric Association; and is an unpaid adviser to the Anxiety and the SNP level. Second, the analyses were restricted to patients Depression Association of America, Consumer Reports, and the Trichotillomania of European ancestry, which limits the generalizability of our College of Medicine and the University of Cincinnati Health Physicians/UC LearningCenter.DrCasutois employed by the University of Cincinnati results; however, this approach has the important advantage Health at the Lindner Center of HOPE and is presently, or has been in the past of reducing the likelihood of confounding by population Laboratories, the Marriott Foundation, Naurex, Shire, and Takeda. DrMcElroyyear, a coinvestigator on research studies sponsored by Cephalon, Forest structure. Reliance on self-reported race/ethnicity is also a is employed by the University of Cincinnati College of Medicine, University of limitation, in that we cannot exclude the possibility of residual Cincinnati Health Physicians/UC Health, and the Lindner Center of HOPE; is a population stratification. Because genome-wide SNP data Bracket, F. Hoffmann-La Roche, MedAvante, Naurex, Novo Nordisk, Shire, and consultant to, or a member ofthe scientific advisory boards of, in the past year, were not available for these samples, more robust methods Sunovion; is presently, or has been in the past year, a principal investigator or such as principal components could not be applied to control Research and Quality in the US Department of Health and Human Services, a coinvestigator on research studies sponsored by the Agency for Healthcare for population stratification. Nevertheless, prior research Alkermes PLC, Cephalon Inc, Forest Laboratories Inc, the Marriott Foundation, has shown that self-reported ancestry is usually a reliable NIMH, Naurex, Orexigen Therapeutics, Shire, and Takeda; and is also an inventor approach for accounting for population structure in candidate Control Disorders and, along with the patent’s assignee, University of Cincinnati, on US Patent No. 6,323,236 B2, Use of Sulfamate Derivatives for Treating Impulse gene studies.50 Third, in most cases, the classification of Cincinnati, Ohio, and has received payments from Johnson & Johnson adult samples as early-onset vs late-onset BD was based on patent.DrJensenis employed by the REACH Institute, New York, New York, and Pharmaceutical Research & Development, which has exclusive rights under the a retrospective review of records and patient report, which in the past 12 months has received charitable gift support from Shire and grant may have been biased or inexact. Also, it was not possible Foundation; is a part owner ofthe psychiatric consulting organization CATCH support from the Marriott Foundation and the Klingenstein Third Generation to characterize numerous, potentially important factors such Services Inc, New York City, New York; and receives book royalties from as co-occurring disorders, treatment history, and functional AmericanPsychiatricPublishing,CivicResearchInstituteInc,BallantineBooks, impairment. Finally, this study was limited to a small number Myriad, Pfizer, NIMH (R01 MH079261), the National Institute on Alcohol Abuse and Guilford Press. DrFrye has received grant support from AssureRx Health, of SNPs. It was not meant to fully characterize the genetics and Alcoholism (P20AA017830) in the National Institutes of Health at the US of early-onset BD; rather, we aimed to explore whether a consultant to Janssen Global Services, Mitsubishi Tanabe, Myriad Genetics, Department of Health and Human Services, and the Mayo Foundation; has been previously identified risk loci might have a more prominent Sunovion, and Teva; has received continuing medical education/travel/ role in early-onset illness. Other important limitations include presentation support from CME Outfitters and Sunovion. Dr Biernacka has the potential differences in comorbidity among cohorts. We on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism in received research funding as a principal investigator from the National Institute were unable to fully characterize and control for comorbidities the National Institutes of Health at the US Department of Health and Human in the present study because of differences between the case Medical Sciences in the National Institutes of Health at the US Department of Services; as a coinvestigator from NIMH and the National Institute of General groups and data collection methods. This may explain the Health and Human Services; and as a co-principal investigator from the Marriott lack of specificity among some of our findings. Finally, as we Foundation for the Mayo Clinic Bipolar Disorder Biobank. DrsVeldic, Joshi, discussed above, the poor longitudinal diagnostic stability other relationship relevant to the subject ofthis article.Nassan, and Cuellar-Barbozaand MssCercyand Geskereport no financial or of BD in childhood presents inherent limitations in the Funding/support:This study was funded by the Marriott Foundation and Mayo interpretation of our findings. Clinic Center for Individualized Medicine. The original TEAM study described In conclusion, this study used GRS analysis to demonstrate MH064846, U01 MH064850, U01 MH064851, U01 MH064868, U01 MH064869, in this manuscript received funding from NIMH cooperative grants U01 that the selected candidate loci contribute primarily to the U01 MH064887, U01 MH064911, and R01 MH051481. Dr Croarkin is supported by risk of early-onset BD rather than to the risk of late-onset NIMHunderAwardNumberK23MH100266. BD. Our results also suggested an association of early-onset Clinic Center for Individualized Medicine, and NIMH) had no role in the study Roleofthesponsor:Thefundingorganizations(MarriottFoundation,Mayo BD with a CACNA1C haplotype. Future studies with larger, design, data collection, analysis, interpretation of results, writing of the report, ethnically diverse samples and more detailed phenotypic orsubmissionofthemanuscript. characterizations will refine the understanding of genetic risk Mental Health, was not involved in the editorial review or decision to publish Disclaimer:Dr Wagner, Section Editor for Focus on Childhood and Adolescent profiles in early-onset BD. this article. The content of this report is solely the responsibility of the authors Funding Information: This study was funded by the Marriott Foundation and Mayo Clinic Center for Individualized Medicine. The original TEAM study described in this manuscript received funding from NIMH cooperative grants U01 MH064846, U01 MH064850, U01 MH064851, U01 MH064868, U01 MH064869, U01 MH064887, U01 MH064911, and R01 MH051481. Dr Croarkin is supported by NIMH under Award Number K23MH100266. Funding Information: bipolar I disorder were rigorously characterized by child and Online first:February 14, 2017. adolescent psychiatrists with a high level of expertise in early-Pfizer, the National Institute of Mental Health (NIMH) (K23 MH100266), the Potential conflicts of interest: DrCroarkinhas received grant support from Publisher Copyright: © Copyright 2017 Physicians Postgraduate Press, Inc.

PY - 2017/11/1

Y1 - 2017/11/1

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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DO - 10.4088/JCP.15m10314

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JF - Journal of Clinical Psychiatry

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Genetic risk score analysis in early-onset bipolar disorder

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