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

Hassan S Dashti; Frank A J L Scheer; Richa Saxena; Marta Garaulet

doi:10.1038/s41366-024-01470-1

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

Int J Obes (Lond). 2024 May;48(5):694-701. doi: 10.1038/s41366-024-01470-1. Epub 2024 Jan 24.

Authors

Hassan S Dashti^{1

2

3

4}, Frank A J L Scheer^{5

6

7}, Richa Saxena^{8

5

9

6}, Marta Garaulet^{10

11

12}

Affiliations

¹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA. hassan.dashti@mgh.harvard.edu.
² Broad Institute, Cambridge, MA, USA. hassan.dashti@mgh.harvard.edu.
³ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. hassan.dashti@mgh.harvard.edu.
⁴ Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA. hassan.dashti@mgh.harvard.edu.
⁵ Broad Institute, Cambridge, MA, USA.
⁶ Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA.
⁷ Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, MA, USA.
⁸ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁹ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹⁰ Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, MA, USA. garaulet@um.es.
¹¹ Department of Physiology, Regional Campus of International Excellence, University of Murcia, 30100, Murcia, Spain. garaulet@um.es.
¹² Biomedical Research Institute of Murcia, IMIB-Arrixaca-UMU, University Clinical Hospital, 30120, Murcia, Spain. garaulet@um.es.

PMID: 38267484
DOI: 10.1038/s41366-024-01470-1

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.

Publication types

Clinical Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Body Mass Index*
Female
Genome-Wide Association Study*
Humans
Male
Middle Aged
Multifactorial Inheritance / genetics
Obesity* / genetics
Polymorphism, Single Nucleotide
Weight Loss* / genetics

Associated data

ClinicalTrials.gov/NCT02829619