Projects per year
Abstract
Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
Original language | English |
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Pages (from-to) | 26-41 |
Number of pages | 16 |
Journal | Nature Genetics |
Volume | 50 |
Issue number | 1 |
Early online date | 22 Dec 2017 |
DOIs | |
Publication status | Published - Jan 2018 |
Keywords
- Genome-wide association studies
- Obesity
ASJC Scopus subject areas
- Genetics
Fingerprint
Dive into the research topics of 'Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity'. Together they form a unique fingerprint.Projects
- 1 Finished
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The Scottish eHealth Informatics Research Centre (E-HIRCs) (Joint with Universities of Aberdeen, Glasgow, Edinburgh, Strathclyde, St Andrews & Leicester and ISD)
Colhoun, H. (Investigator), Donnan, P. (Investigator), Guthrie, B. (Investigator), Jefferson, E. (Investigator), MacDonald, T. (Investigator), McCowan, C. (Investigator), Morris, A. (Investigator), Pearson, E. (Investigator), Sullivan, F. (Investigator) & Swedlow, J. (Investigator)
1/03/13 → 31/12/18
Project: Research
Research output
- 255 Citations
- 2 Article
-
Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
Turcot, V., Lu, Y., Highland, H. M., Schurmann, C., Justice, A. E., Fine, R. S., Bradfield, J. P., Esko, T., Giri, A., Graff, M., Guo, X., Hendricks, A. E., Karaderi, T., Lempradl, A., Locke, A. E., Mahajan, A., Marouli, E., Sivapalaratnam, S., Young, K. L. & Alfred, T. & 40 others, , May 2018, In: Nature Genetics. 50, 5, p. 765-766 2 p.Research output: Contribution to journal › Article › peer-review
1 Citation (Scopus) -
Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
Turcot, V., Lu, Y., Highland, H. M., Schurmann, C., Justice, A. E., Fine, R. S., Bradfield, J. P., Esko, T., Giri, A., Graff, M., Guo, X., Hendricks, A. E., Karaderi, T., Lempradl, A., Locke, A. E., Mahajan, A., Marouli, E., Sivapalaratnam, S., Young, K. L. & Alfred, T. & 40 others, , May 2018, In: Nature Genetics. 50, 5, p. 766-767 2 p.Research output: Contribution to journal › Article › peer-review
7 Citations (Scopus)