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Genetics and Epigenetics

Impact of polygenic score for BMI on weight loss effectiveness and genome-wide association analysis

International Journal of Obesity volume 48, pages 694–701 (2024)Cite this article

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A Correction to this article was published on 08 March 2024

This article has been updated

Abstract

Background

While environmental factors play an important role in weight loss effectiveness, genetics may also influence its success. We examined whether a genome-wide polygenic score for BMI was associated with weight loss effectiveness and aimed to identify common genetic variants associated with weight loss.

Methods

Participants in the ONTIME study (n = 1210) followed a uniform, multimodal behavioral weight-loss intervention. We first tested associations between a genome-wide polygenic score for higher BMI and weight loss effectiveness (total weight loss, rate of weight loss, and attrition). We then conducted a genome-wide association study (GWAS) for weight loss in the ONTIME study and performed the largest weight loss meta-analysis with earlier studies (n = 3056). Lastly, we ran exploratory GWAS in the ONTIME study for other weight loss outcomes and related factors.

Results

We found that each standard deviation increment in the polygenic score was associated with a decrease in the rate of weight loss (Beta (95% CI) = −0.04 kg per week (−0.06, −0.01); P = 3.7 × 10−03) and with higher attrition after adjusting by treatment duration. No associations reached genome-wide significance in meta-analysis with previous GWAS studies for weight loss. However, associations in the ONTIME study showed effects consistent with published studies for rs545936 (MIR486/NKX6.3/ANK1), a previously noted weight loss locus. In the meta-analysis, each copy of the minor A allele was associated with 0.12 (0.03) kg/m2 higher BMI at week five of treatment (P = 3.9 × 10−06). In the ONTIME study, we also identified two genome-wide significant (P < 5×10−08) loci for the rate of weight loss near genes implicated in lipolysis, body weight, and metabolic regulation: rs146905606 near NFIP1/SPRY4/FGF1; and rs151313458 near LSAMP.

Conclusion

Our findings are expected to help in developing personalized weight loss approaches based on genetics.

Clinical trial registration

Obesity, Nutrigenetics, Timing, and Mediterranean (ONTIME; clinicaltrials.gov: NCT02829619) study.

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Fig. 1: Weight loss trajectory in the ONTIME study.
Fig. 2: Manhattan plot and QQ plot for genome-wide meta-analysis of weight loss (BMI at week 5) in participants of European ancestry from the ONTIME, Ottawa, and DiOGenes studies (n = 3056).
Fig. 3: Genome-wide association meta-analysis results for weight loss.

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Data availability

Summary statistics from this genome-wide association study can be downloaded from the Common Metabolic Diseases Knowledge Portal (https://hugeamp.org/).

Change history

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Funding

Funding

The ONTIME study received the following funding: PID2020-112768RB-I00 funded by MCIN/AEI/10.13039/501100011033. The Autonomous Community of the Region of Murcia through the Seneca Foundation (20795/PI/18) and NIDDK R01DK105072 granted to MG. RS was supported by NIH R01DK107859 and Phyllis and Jerome Lyle Rappaport Massachusetts General Hospital Research Scholar Award. RS and FAJLS were supported by NIH R01DK102696 and R01DK105072. FAJLS was further supported by R01DK099512, R01HL118601, R01HL140574, and R01HL153969. HSD is supported by NIH K99HL153795.

Author information

Authors and Affiliations

  1. Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    Hassan S. Dashti & Richa Saxena

  2. Broad Institute, Cambridge, MA, USA

    Hassan S. Dashti, Frank A. J. L. Scheer & Richa Saxena

  3. Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Hassan S. Dashti & Richa Saxena

  4. Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA

    Hassan S. Dashti, Frank A. J. L. Scheer & Richa Saxena

  5. Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women’s Hospital, Boston, MA, USA

    Frank A. J. L. Scheer & Marta Garaulet

  6. Department of Physiology, Regional Campus of International Excellence, University of Murcia, 30100, Murcia, Spain

    Marta Garaulet

  7. Biomedical Research Institute of Murcia, IMIB-Arrixaca-UMU, University Clinical Hospital, 30120, Murcia, Spain

    Marta Garaulet

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  1. Hassan S. Dashti
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Contributions

All authors listed fully meet the criteria for authorship. The authors’ responsibilities were as follows: Conceptualization, HSD, RS, and MG; methodology, HSD, FAJLS, RS, and MG; formal analysis, HSD and MG; resources HSD and MG; data curation MG; writing— original draft preparation, HSD and MG; writing—review and editing, HSD, FAJLS, RS, and MG; visualization, HSD and MG; supervision, RS and MG. All authors have read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Hassan S. Dashti or Marta Garaulet.

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Competing interests

FAJLS served on the Board of Directors for the Sleep Research Society and has received consulting fees from the University of Alabama at Birmingham and Morehouse School of Medicine. FAJLS interests were reviewed and managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict-of-interest policies. FAJLS consultancies are not related to the current work. RS is a cofounder of Magnet Biomedicine, not related to the current work. The other authors declare no conflict of interest. All authors have read the Journal’s policy on disclosure of potential conflicts of interest.

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Dashti, H.S., Scheer, F.A.J.L., Saxena, R. et al. Impact of polygenic score for BMI on weight loss effectiveness and genome-wide association analysis. Int J Obes 48, 694–701 (2024). https://doi.org/10.1038/s41366-024-01470-1

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