A high throughput, functional screen of human Body Mass Index GWAS loci using tissue-specific RNAi Drosophila melanogaster crosses
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Baranski, T.J, et al. A High Throughput, Functional Screen of Human Body Mass Index Gwas Loci Using Tissue-specific Rnai Drosophila Melanogaster Crosses. 2018. https://doi.org/10.17615/w9v0-ch68APA
Baranski, T., Kraja, A., Fink, J., Feitosa, M., Lenzini, P., Borecki, I., Liu, C., Cupples, L., North, K., & Province, M. (2018). A high throughput, functional screen of human Body Mass Index GWAS loci using tissue-specific RNAi Drosophila melanogaster crosses. https://doi.org/10.17615/w9v0-ch68Chicago
Baranski, T.J., A.T Kraja, J.L Fink, M Feitosa, P.A Lenzini, I.B Borecki, C. T Liu et al. 2018. A High Throughput, Functional Screen of Human Body Mass Index Gwas Loci Using Tissue-Specific Rnai Drosophila Melanogaster Crosses. https://doi.org/10.17615/w9v0-ch68- Creator
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Baranski, T.J.
- Other Affiliation: Washington University School of Medicine
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Kraja, A.T.
- Other Affiliation: Washington University School of Medicine
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Fink, J.L.
- Other Affiliation: Washington University
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Feitosa, M.
- Other Affiliation: Washington University School of Medicine
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Lenzini, P.A.
- Other Affiliation: Washington University School of Medicine
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Borecki, I.B.
- Other Affiliation: University of Washington
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Liu, C.-T.
- Other Affiliation: Boston University School of Public Health
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Cupples, L.A.
- Other Affiliation: Boston University School of Public Health
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North, K.E.
- Affiliation: Gillings School of Global Public Health, Department of Epidemiology
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Province, M.A.
- Other Affiliation: Washington University School of Medicine
- Abstract
- Human GWAS of obesity have been successful in identifying loci associated with adiposity, but for the most part, these are non-coding SNPs whose function, or even whose gene of action, is unknown. To help identify the genes on which these human BMI loci may be operating, we conducted a high throughput screen in Drosophila melanogaster. Starting with 78 BMI loci from two recently published GWAS meta-analyses, we identified fly orthologs of all nearby genes (± 250KB). We crossed RNAi knockdown lines of each gene with flies containing tissue-specific drivers to knock down (KD) the expression of the genes only in the brain and the fat body. We then raised the flies on a control diet and compared the amount of fat/triglyceride in the tissue-specific KD group compared to the driver-only control flies. 16 of the 78 BMI GWAS loci could not be screened with this approach, as no gene in the 500-kb region had a fly ortholog. Of the remaining 62 GWAS loci testable in the fly, we found a significant fat phenotype in the KD flies for at least one gene for 26 loci (42%) even after correcting for multiple comparisons. By contrast, the rate of significant fat phenotypes in RNAi KD found in a recent genome-wide Drosophila screen (Pospisilik et al. (2010) is ~5%. More interestingly, for 10 of the 26 positive regions, we found that the nearest gene was not the one that showed a significant phenotype in the fly. Specifically, our screen suggests that for the 10 human BMI SNPs rs11057405, rs205262, rs9925964, rs9914578, rs2287019, rs11688816, rs13107325, rs7164727, rs17724992, and rs299412, the functional genes may NOT be the nearest ones (CLIP1, C6orf106, KAT8, SMG6, QPCTL, EHBP1, SLC39A8, ADPGK /ADPGK-AS1, PGPEP1, KCTD15, respectively), but instead, the specific nearby cis genes are the functional target (namely: ZCCHC8, VPS33A, RSRC2; SPDEF, NUDT3; PAGR1; SETD1, VKORC1; SGSM2, SRR; VASP, SIX5; OTX1; BANK1; ARIH1; ELL; CHST8, respectively). The study also suggests further functional experiments to elucidate mechanism of action for genes evolutionarily conserved for fat storage.
- Date of publication
- 2018
- Keyword
- EHBP1 gene
- Polymorphism, Single Nucleotide
- SGSM2 gene
- Adipose Tissue
- SRR gene
- KAT8 gene
- C6orf106 gene
- quantitative trait locus
- animal
- mouse
- gene locus
- Animals
- cross breeding
- body mass
- Article
- ADPGK gene
- adipose tissue
- SETD1 gene
- ADPGK AS1 gene
- gene
- OTX1 gene
- ARIH1 gene
- SLC39A8 gene
- PAGR1 gene
- controlled study
- single nucleotide polymorphism
- Drosophila melanogaster
- obesity
- genetics
- genome-wide association study
- CHST8 gene
- RSRC2 gene
- female
- adult
- male
- RNA Interference
- Mice
- QPCTL gene
- nonhuman
- ZCCHC8 gene
- phenotype
- intron
- Humans
- Obesity
- gene knockdown
- VKORC1 gene
- PGPEP1 gene
- VPS33A gene
- RNA interference
- Genome-Wide Association Study
- Body Mass Index
- SPDEF gene
- human tissue
- KCTD15 gene
- human
- SIX5 gene
- VASP gene
- Crosses, Genetic
- CLIP1 gene
- SMG6 gene
- NUDT3 gene
- ELL gene
- Quantitative Trait Loci
- BANK1 gene
- genetic conservation
- DOI
- Identifier
- Resource type
- Article
- Rights statement
- In Copyright
- License
- Attribution 4.0 International
- Journal title
- PLoS Genetics
- Journal volume
- 14
- Journal issue
- 4
- Language
- English
- Version
- Publisher
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