TOPLINE

Genetically increased expression of glucagon-like peptide-1 receptor (GLP1R) was associated with a 7% higher risk for male pattern hair loss (MPHL) in a study. The association persisted after adjusting for waist-to-hip ratio, blood pressure, insulin-like growth factor 1 (IGF-1), and testosterone.

METHODOLOGY

• Researchers conducted a two-sample Mendelian randomization analysis using publicly available genome-wide association study summary statistics to evaluate the association between genetic proxies of GLP1R expression and the risk for androgenetic alopecia.
• A total of 205,327 individuals of European ancestry were included in the MPHL outcome dataset, while genetic proxies for GLP1R expression were derived from 31,684 individuals of European ancestry.
• The instrument comprised 22 independent cis-expression quantitative trait loci from whole blood at genome-wide significance, with an F-statistic of 53.0 supporting strong instrument relevance.
• Primary analysis used inverse-variance weighted Mendelian randomization under a multiplicative random-effects model, with sensitivity analyses including weighted median, simple median, robust inverse-variance weighted, and penalized inverse-variance weighted approaches.
• Multivariable Mendelian randomization adjusted for genetic proxies of waist-to-hip ratio adjusted for BMI, systolic blood pressure, serum IGF-1, and testosterone to assess independence from candidate mediators.

TAKEAWAY

• Genetically predicted GLP1R expression was significantly associated with increased risk for MPHL (inverse-variance weighted odds ratio [OR], 1.07; P = 1 × 10^-23).
• Directionally consistent estimates were seen with weighted median (OR, 1.07; P = 6.80 × 10^-6), simple median (OR, 1.07; P = 6.80 × 10^-6), penalized inverse-variance weighted (OR, 1.07; P = 5.95 × 10^-9), and robust inverse-variance weighted (OR, 1.06; P = 2.65 × 10^-4) methods.
• After multivariable adjustment for waist-to-hip ratio adjusted for BMI, the association remained significant (OR, 1.1; P = 8.32 × 10^-14), as did adjustments for systolic blood pressure (OR, 1.07; P = 6.01 × 10^-29), IGF-1 (OR, 1.08; P = 2.54 × 10^-10), and testosterone (OR, 1.1; P = 1.17 × 10^-9).
• The association between GLP1R expression and the risk for MPHL persisted in the fully adjusted model (OR, 1.08; P = 2.90 × 10^-10).

IN PRACTICE

"[T]hese findings support a potential causal relationship between increased GLP-1R expression and MPHL risk," the authors wrote. "The observed effect size is modest and, while statistically robust, its clinical relevance remains uncertain, particularly given the complexity of translating genetically proxied, lifelong perturbations in gene expression to clinical responses following short-term pharmacologic modulation," they added. "Future genetic studies could help clarify whether GLP1R expression and MPHL susceptibility share the same underlying causal variants."

SOURCE

The study was led by Ravi Ramessur, MD, PhD, Department of Dermatology and Center for Clinical Sciences in Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, and Archie Spindler, BA, Department of Dermatology, New York University Grossman School of Medicine, New York. It was published online on September 3 in the Journal of Investigative Dermatology.

LIMITATIONS

The exposure instrument was derived from a mixed-sex population, whereas the outcome data were restricted to men, which could have introduced bias. The whole-blood instrument did not capture scalp- or follicle-specific expression, and colocalization analysis did not support a shared causal variant at this locus. Genetic proxies reflected lifelong expression differences rather than short-term drug exposure, and findings may not be generalizable to female pattern hair loss or telogen effluvium.

DISCLOSURES

This study was supported by the National Institutes of Health. The authors reported being investigators and consultants for multiple pharmaceutical and biotechnology companies, including Lilly, Pfizer, Priovant, and Veradermics. Full disclosures are available in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.