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 language | English (US) |
|---|---|
| Journal | Schizophrenia Research |
| DOIs | |
| State | Accepted/In press - Jan 1 2019 |
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Keywords
- Antipsychotic-induced weight gain (AIWG)
- Diacylglycerol kinase beta (DGKB)
- GWAS
- Schizophrenia
ASJC Scopus subject areas
- Psychiatry and Mental health
- Biological Psychiatry
Cite this
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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 journal › Article
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.
KW - Antipsychotic-induced weight gain (AIWG)
KW - Diacylglycerol kinase beta (DGKB)
KW - GWAS
KW - Schizophrenia
UR - http://www.scopus.com/inward/record.url?scp=85070870327&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85070870327&partnerID=8YFLogxK
U2 - 10.1016/j.schres.2019.07.022
DO - 10.1016/j.schres.2019.07.022
M3 - Article
JO - Schizophrenia Research
JF - Schizophrenia Research
SN - 0920-9964
ER -