Genome-wide association study on antipsychotic-induced weight gain in Europeans and African-Americans

Malgorzata Maciukiewicz, Arun K. Tiwari, Clement C. Zai, I. Gorbovskaya, Christopher P. Laughlin, Erika L. Nurmi, Jeffrey A. Liebermann, Herbert Y Meltzer, James L. Kennedy, Daniel J. Müller*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Background: Antipsychotic (AP) medications are the first line of treatment for schizophrenia. However, most conferr a risk of antipsychotic-induced weight gain (AIWG). The objective of this investigation was to conduct a genome-wide association study (GWAS) of AIWG, followed by comprehensive, post-GWAS approaches. Methods: We investigated n = 201 schizophrenia or schizoaffective disorder patients of European and African American ancestry who were treated primarily with clozapine or olanzapine. We conducted a genome-wide association analysis for AIWG, defined primarily as a percentage of weight change from baseline. Results: When examining Europeans (n = 147), we noticed an association between rs62097526 (β = 0.39, p = 3.59 × 10−6, CADD = 2.213) variant, located downstream of the CIDEA gene, which is considered a risk factor for AIWG. In the entire sample, we observed a significant association between rs1525085 (β = 0.411, p = 3.15 × 10−9) variant of the DGKB gene and AIWG. The association was nominally significant in Europeans (β = 0.271, p = 0.002) and African Americans (β = 0.579, p = 5.73 × 10−5) with the same risk allele. Our top genes (p < 5 × 10−5) were enriched in the GWAS catalog for the risk of obesity and interacted with the known risk factors for obesity (G6PD) and diabetes (IRS1). In addition, these genes are targeted by miRNAs related to schizophrenia (mir-34a) and obesity (mir-19b). However, our polygenic risk score analyses did not provide support for major genetic overlap between obesity and the risk of AIWG. Conclusions: In summary, we propose that the CIDEA and DGKB genes are risk factors for AIWG in transethnic populations. Additionally, our evidence suggests that the G6PD and IRS1 gene-related pathways might be involved in AIWG.

Original languageEnglish (US)
JournalSchizophrenia Research
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Genome-Wide Association Study
African Americans
Antipsychotic Agents
Weight Gain
Obesity
Genes
Schizophrenia
olanzapine
Clozapine
MicroRNAs
Psychotic Disorders
Alleles
Weights and Measures

Keywords

  • Antipsychotic-induced weight gain (AIWG)
  • Diacylglycerol kinase beta (DGKB)
  • GWAS
  • Schizophrenia

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry

Cite this

Maciukiewicz, M., Tiwari, A. K., Zai, C. C., Gorbovskaya, I., Laughlin, C. P., Nurmi, E. L., ... Müller, D. J. (Accepted/In press). Genome-wide association study on antipsychotic-induced weight gain in Europeans and African-Americans. Schizophrenia Research. https://doi.org/10.1016/j.schres.2019.07.022
Maciukiewicz, Malgorzata ; Tiwari, Arun K. ; Zai, Clement C. ; Gorbovskaya, I. ; Laughlin, Christopher P. ; Nurmi, Erika L. ; Liebermann, Jeffrey A. ; Meltzer, Herbert Y ; Kennedy, James L. ; Müller, Daniel J. / Genome-wide association study on antipsychotic-induced weight gain in Europeans and African-Americans. In: Schizophrenia Research. 2019.
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abstract = "Background: Antipsychotic (AP) medications are the first line of treatment for schizophrenia. However, most conferr a risk of antipsychotic-induced weight gain (AIWG). The objective of this investigation was to conduct a genome-wide association study (GWAS) of AIWG, followed by comprehensive, post-GWAS approaches. Methods: We investigated n = 201 schizophrenia or schizoaffective disorder patients of European and African American ancestry who were treated primarily with clozapine or olanzapine. We conducted a genome-wide association analysis for AIWG, defined primarily as a percentage of weight change from baseline. Results: When examining Europeans (n = 147), we noticed an association between rs62097526 (β = 0.39, p = 3.59 × 10−6, CADD = 2.213) variant, located downstream of the CIDEA gene, which is considered a risk factor for AIWG. In the entire sample, we observed a significant association between rs1525085 (β = 0.411, p = 3.15 × 10−9) variant of the DGKB gene and AIWG. The association was nominally significant in Europeans (β = 0.271, p = 0.002) and African Americans (β = 0.579, p = 5.73 × 10−5) with the same risk allele. Our top genes (p < 5 × 10−5) were enriched in the GWAS catalog for the risk of obesity and interacted with the known risk factors for obesity (G6PD) and diabetes (IRS1). In addition, these genes are targeted by miRNAs related to schizophrenia (mir-34a) and obesity (mir-19b). However, our polygenic risk score analyses did not provide support for major genetic overlap between obesity and the risk of AIWG. Conclusions: In summary, we propose that the CIDEA and DGKB genes are risk factors for AIWG in transethnic populations. Additionally, our evidence suggests that the G6PD and IRS1 gene-related pathways might be involved in AIWG.",
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Maciukiewicz, M, Tiwari, AK, Zai, CC, Gorbovskaya, I, Laughlin, CP, Nurmi, EL, Liebermann, JA, Meltzer, HY, Kennedy, JL & Müller, DJ 2019, 'Genome-wide association study on antipsychotic-induced weight gain in Europeans and African-Americans', Schizophrenia Research. https://doi.org/10.1016/j.schres.2019.07.022

Genome-wide association study on antipsychotic-induced weight gain in Europeans and African-Americans. / Maciukiewicz, Malgorzata; Tiwari, Arun K.; Zai, Clement C.; Gorbovskaya, I.; Laughlin, Christopher P.; Nurmi, Erika L.; Liebermann, Jeffrey A.; Meltzer, Herbert Y; Kennedy, James L.; Müller, Daniel J.

In: Schizophrenia Research, 01.01.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genome-wide association study on antipsychotic-induced weight gain in Europeans and African-Americans

AU - Maciukiewicz, Malgorzata

AU - Tiwari, Arun K.

AU - Zai, Clement C.

AU - Gorbovskaya, I.

AU - Laughlin, Christopher P.

AU - Nurmi, Erika L.

AU - Liebermann, Jeffrey A.

AU - Meltzer, Herbert Y

AU - Kennedy, James L.

AU - Müller, Daniel J.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: Antipsychotic (AP) medications are the first line of treatment for schizophrenia. However, most conferr a risk of antipsychotic-induced weight gain (AIWG). The objective of this investigation was to conduct a genome-wide association study (GWAS) of AIWG, followed by comprehensive, post-GWAS approaches. Methods: We investigated n = 201 schizophrenia or schizoaffective disorder patients of European and African American ancestry who were treated primarily with clozapine or olanzapine. We conducted a genome-wide association analysis for AIWG, defined primarily as a percentage of weight change from baseline. Results: When examining Europeans (n = 147), we noticed an association between rs62097526 (β = 0.39, p = 3.59 × 10−6, CADD = 2.213) variant, located downstream of the CIDEA gene, which is considered a risk factor for AIWG. In the entire sample, we observed a significant association between rs1525085 (β = 0.411, p = 3.15 × 10−9) variant of the DGKB gene and AIWG. The association was nominally significant in Europeans (β = 0.271, p = 0.002) and African Americans (β = 0.579, p = 5.73 × 10−5) with the same risk allele. Our top genes (p < 5 × 10−5) were enriched in the GWAS catalog for the risk of obesity and interacted with the known risk factors for obesity (G6PD) and diabetes (IRS1). In addition, these genes are targeted by miRNAs related to schizophrenia (mir-34a) and obesity (mir-19b). However, our polygenic risk score analyses did not provide support for major genetic overlap between obesity and the risk of AIWG. Conclusions: In summary, we propose that the CIDEA and DGKB genes are risk factors for AIWG in transethnic populations. Additionally, our evidence suggests that the G6PD and IRS1 gene-related pathways might be involved in AIWG.

AB - Background: Antipsychotic (AP) medications are the first line of treatment for schizophrenia. However, most conferr a risk of antipsychotic-induced weight gain (AIWG). The objective of this investigation was to conduct a genome-wide association study (GWAS) of AIWG, followed by comprehensive, post-GWAS approaches. Methods: We investigated n = 201 schizophrenia or schizoaffective disorder patients of European and African American ancestry who were treated primarily with clozapine or olanzapine. We conducted a genome-wide association analysis for AIWG, defined primarily as a percentage of weight change from baseline. Results: When examining Europeans (n = 147), we noticed an association between rs62097526 (β = 0.39, p = 3.59 × 10−6, CADD = 2.213) variant, located downstream of the CIDEA gene, which is considered a risk factor for AIWG. In the entire sample, we observed a significant association between rs1525085 (β = 0.411, p = 3.15 × 10−9) variant of the DGKB gene and AIWG. The association was nominally significant in Europeans (β = 0.271, p = 0.002) and African Americans (β = 0.579, p = 5.73 × 10−5) with the same risk allele. Our top genes (p < 5 × 10−5) were enriched in the GWAS catalog for the risk of obesity and interacted with the known risk factors for obesity (G6PD) and diabetes (IRS1). In addition, these genes are targeted by miRNAs related to schizophrenia (mir-34a) and obesity (mir-19b). However, our polygenic risk score analyses did not provide support for major genetic overlap between obesity and the risk of AIWG. Conclusions: In summary, we propose that the CIDEA and DGKB genes are risk factors for AIWG in transethnic populations. Additionally, our evidence suggests that the G6PD and IRS1 gene-related pathways might be involved in AIWG.

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KW - Diacylglycerol kinase beta (DGKB)

KW - GWAS

KW - Schizophrenia

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