A Drosophila functional evaluation of candidates from human genome-wide association studies of type 2 diabetes and related metabolic traits identifies tissue-specific roles for dHHEX

Jay Pendse; Prasanna V. Ramachandran; Jianbo Na; Narisu Narisu; Jill L. Fink; Ross L. Cagan; Francis S. Collins; Thomas J. Baranski

doi:10.1186/1471-2164-14-136

A Drosophila functional evaluation of candidates from human genome-wide association studies of type 2 diabetes and related metabolic traits identifies tissue-specific roles for dHHEX

Jay Pendse, Prasanna V. Ramachandran, Jianbo Na, Narisu Narisu, Jill L. Fink, Ross L. Cagan, Francis S. Collins, Thomas J. Baranski

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Abstract

Background: Genome-wide association studies (GWAS) identify regions of the genome that are associated with particular traits, but do not typically identify specific causative genetic elements. For example, while a large number of single nucleotide polymorphisms associated with type 2 diabetes (T2D) and related traits have been identified by human GWAS, only a few genes have functional evidence to support or to rule out a role in cellular metabolism or dietary interactions. Here, we use a recently developed Drosophila model in which high-sucrose feeding induces phenotypes similar to T2D to assess orthologs of human GWAS-identified candidate genes for risk of T2D and related traits.Results: Disrupting orthologs of certain T2D candidate genes (HHEX, THADA, PPARG, KCNJ11) led to sucrose-dependent toxicity. Tissue-specific knockdown of the HHEX ortholog dHHEX (CG7056) directed metabolic defects and enhanced lethality; for example, fat-body-specific loss of dHHEX led to increased hemolymph glucose and reduced insulin sensitivity.Conclusion: Candidate genes identified in human genetic studies of metabolic traits can be prioritized and functionally characterized using a simple Drosophila approach. To our knowledge, this is the first large-scale effort to study the functional interaction between GWAS-identified candidate genes and an environmental risk factor such as diet in a model organism system.

Original language	English
Article number	136
Journal	BMC genomics
Volume	14
Issue number	1
DOIs	https://doi.org/10.1186/1471-2164-14-136
State	Published - Feb 27 2013

Keywords

Diabetes mellitus, type 2
Drosophila melanogaster
Dyslipidemias
Genome-wide association study
HHEX protein, Human
High-throughput screening assays
Hyperglycemia
Phylogeny
Reverse genetics

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10.1186/1471-2164-14-136

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Pendse, J., Ramachandran, P. V., Na, J., Narisu, N., Fink, J. L., Cagan, R. L., Collins, F. S., & Baranski, T. J. (2013). A Drosophila functional evaluation of candidates from human genome-wide association studies of type 2 diabetes and related metabolic traits identifies tissue-specific roles for dHHEX. BMC genomics, 14(1), Article 136. https://doi.org/10.1186/1471-2164-14-136

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title = "A Drosophila functional evaluation of candidates from human genome-wide association studies of type 2 diabetes and related metabolic traits identifies tissue-specific roles for dHHEX",

abstract = "Background: Genome-wide association studies (GWAS) identify regions of the genome that are associated with particular traits, but do not typically identify specific causative genetic elements. For example, while a large number of single nucleotide polymorphisms associated with type 2 diabetes (T2D) and related traits have been identified by human GWAS, only a few genes have functional evidence to support or to rule out a role in cellular metabolism or dietary interactions. Here, we use a recently developed Drosophila model in which high-sucrose feeding induces phenotypes similar to T2D to assess orthologs of human GWAS-identified candidate genes for risk of T2D and related traits.Results: Disrupting orthologs of certain T2D candidate genes (HHEX, THADA, PPARG, KCNJ11) led to sucrose-dependent toxicity. Tissue-specific knockdown of the HHEX ortholog dHHEX (CG7056) directed metabolic defects and enhanced lethality; for example, fat-body-specific loss of dHHEX led to increased hemolymph glucose and reduced insulin sensitivity.Conclusion: Candidate genes identified in human genetic studies of metabolic traits can be prioritized and functionally characterized using a simple Drosophila approach. To our knowledge, this is the first large-scale effort to study the functional interaction between GWAS-identified candidate genes and an environmental risk factor such as diet in a model organism system.",

keywords = "Diabetes mellitus, type 2, Drosophila melanogaster, Dyslipidemias, Genome-wide association study, HHEX protein, Human, High-throughput screening assays, Hyperglycemia, Phylogeny, Reverse genetics",

author = "Jay Pendse and Ramachandran, {Prasanna V.} and Jianbo Na and Narisu Narisu and Fink, {Jill L.} and Cagan, {Ross L.} and Collins, {Francis S.} and Baranski, {Thomas J.}",

note = "Funding Information: We thank Vivek A. Rudrapatna, Ruth I. Johnson, Susumu Hirabayashi, Erdem Bangi, Tirtha Kamal Das, Laura Palanker Musselman, Dac Anh Nguyen, Lori Bonnycastle, Michael Stitzel, Michael Erdos, and Laura Scott for advice and helpful discussions, and countless members of the free and open source software community for valuable guidance and code samples. This research was supported by NIH grants R21 DK069940 (RLC), P60 DK20579 (Washington University DRTC, TJB), and P20 RR020643 (TJB), as well as by grants from the NephCure Foundation (JN and RLC) and from the American Diabetes Association (JN and RLC). JP was supported in part by NIGMS Training Grant T32 GM-62754, NIH. NN and FSC were supported by the intramural program of NHGRI, NIH.",

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month = feb,

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doi = "10.1186/1471-2164-14-136",

language = "English",

volume = "14",

journal = "BMC genomics",

issn = "1471-2164",

number = "1",

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TY - JOUR

T1 - A Drosophila functional evaluation of candidates from human genome-wide association studies of type 2 diabetes and related metabolic traits identifies tissue-specific roles for dHHEX

AU - Pendse, Jay

AU - Ramachandran, Prasanna V.

AU - Na, Jianbo

AU - Narisu, Narisu

AU - Fink, Jill L.

AU - Cagan, Ross L.

AU - Collins, Francis S.

AU - Baranski, Thomas J.

N1 - Funding Information: We thank Vivek A. Rudrapatna, Ruth I. Johnson, Susumu Hirabayashi, Erdem Bangi, Tirtha Kamal Das, Laura Palanker Musselman, Dac Anh Nguyen, Lori Bonnycastle, Michael Stitzel, Michael Erdos, and Laura Scott for advice and helpful discussions, and countless members of the free and open source software community for valuable guidance and code samples. This research was supported by NIH grants R21 DK069940 (RLC), P60 DK20579 (Washington University DRTC, TJB), and P20 RR020643 (TJB), as well as by grants from the NephCure Foundation (JN and RLC) and from the American Diabetes Association (JN and RLC). JP was supported in part by NIGMS Training Grant T32 GM-62754, NIH. NN and FSC were supported by the intramural program of NHGRI, NIH.

PY - 2013/2/27

Y1 - 2013/2/27

N2 - Background: Genome-wide association studies (GWAS) identify regions of the genome that are associated with particular traits, but do not typically identify specific causative genetic elements. For example, while a large number of single nucleotide polymorphisms associated with type 2 diabetes (T2D) and related traits have been identified by human GWAS, only a few genes have functional evidence to support or to rule out a role in cellular metabolism or dietary interactions. Here, we use a recently developed Drosophila model in which high-sucrose feeding induces phenotypes similar to T2D to assess orthologs of human GWAS-identified candidate genes for risk of T2D and related traits.Results: Disrupting orthologs of certain T2D candidate genes (HHEX, THADA, PPARG, KCNJ11) led to sucrose-dependent toxicity. Tissue-specific knockdown of the HHEX ortholog dHHEX (CG7056) directed metabolic defects and enhanced lethality; for example, fat-body-specific loss of dHHEX led to increased hemolymph glucose and reduced insulin sensitivity.Conclusion: Candidate genes identified in human genetic studies of metabolic traits can be prioritized and functionally characterized using a simple Drosophila approach. To our knowledge, this is the first large-scale effort to study the functional interaction between GWAS-identified candidate genes and an environmental risk factor such as diet in a model organism system.

AB - Background: Genome-wide association studies (GWAS) identify regions of the genome that are associated with particular traits, but do not typically identify specific causative genetic elements. For example, while a large number of single nucleotide polymorphisms associated with type 2 diabetes (T2D) and related traits have been identified by human GWAS, only a few genes have functional evidence to support or to rule out a role in cellular metabolism or dietary interactions. Here, we use a recently developed Drosophila model in which high-sucrose feeding induces phenotypes similar to T2D to assess orthologs of human GWAS-identified candidate genes for risk of T2D and related traits.Results: Disrupting orthologs of certain T2D candidate genes (HHEX, THADA, PPARG, KCNJ11) led to sucrose-dependent toxicity. Tissue-specific knockdown of the HHEX ortholog dHHEX (CG7056) directed metabolic defects and enhanced lethality; for example, fat-body-specific loss of dHHEX led to increased hemolymph glucose and reduced insulin sensitivity.Conclusion: Candidate genes identified in human genetic studies of metabolic traits can be prioritized and functionally characterized using a simple Drosophila approach. To our knowledge, this is the first large-scale effort to study the functional interaction between GWAS-identified candidate genes and an environmental risk factor such as diet in a model organism system.

KW - Diabetes mellitus, type 2

KW - Drosophila melanogaster

KW - Dyslipidemias

KW - Genome-wide association study

KW - HHEX protein, Human

KW - High-throughput screening assays

KW - Hyperglycemia

KW - Phylogeny

KW - Reverse genetics

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DO - 10.1186/1471-2164-14-136

M3 - Article

C2 - 23445342

AN - SCOPUS:84874255352

SN - 1471-2164

VL - 14

JO - BMC genomics

JF - BMC genomics

IS - 1

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ER -

A Drosophila functional evaluation of candidates from human genome-wide association studies of type 2 diabetes and related metabolic traits identifies tissue-specific roles for dHHEX

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