GoKawiilOverview of study recruitment
Participants in this study were recruited from the customer base of 23andMe. Participants provided informed consent and volunteered to participate in the research online, under a protocol approved by the external Association for the Accreditation of Human Research Protection Programs-accredited Salus Institutional Review Board (https://www.versiticlinicaltrials.org/salusirb). Participants were included in the analysis on the basis of consent status verified at the time data analyses were initiated.
The 23andMe GLP1 survey was launched to research participants in August 2024. The survey aimed to capture participants’ experiences with GLP1 receptor agonist medication, and was targeted to 23andMe participants who had previously responded in the affirmative to the question, ‘Have you ever taken prescription medications to help you lose weight?’. The survey included questions regarding drug brand, dosing regimen, time on treatment, efficacy (including pre-treatment weight and weight on treatment), and side effects, as well as reasons for pursuing or stopping GLP1 treatment. We focused the survey and subsequent analysis on primarily six drug varieties; Ozempic, Wegovy, compounded semaglutide, Mounjaro, Zepbound and compounded tirzepatide, the first three of which represent variations of semaglutide, and the last three represent variations in tirzepatide. A full list of survey questions can be found in Supplementary Table 24.
Phenotype definitions
Using the information derived from the surveys, we defined phenotypes that aimed to capture aspects of drug efficacy and side effects. We defined our efficacy phenotype as the contrast between pre-treatment BMI to post-treatment BMI (or current BMI, if treatment is on-going). In general, for study participants who reported taking more than one GLP1 medication, we selected the GLP1 medication that they reported taking for the longest period of time. Specifically, we defined a percentage BMI change phenotype as:
$${{\rm{\Delta BMI}}}_{ \% }=100({\mathrm{BMI}}_{2}-{\mathrm{BMI}}_{1})/{\mathrm{BMI}}_{1}$$
where BMI 1 and BMI 2 represent pre-treatment and post-treatment BMI, respectively, measured in weight in kilograms per height in metres squared. We applied quality control filters to people with weight less than 36 kg or greater than 181 kg, height less than 1.39 m or greater than 2.06 m, BMI less than 14 kg m−2 or greater than 70 kg m−2, or age less than 18 years. In aggregate, these initial filters removed 80 people (0.29%). Inspection of the ΔBMI % phenotype revealed a heavy tailed distribution, so we further quality controlled the ΔBMI % phenotype to remove outlier participants with BMI changes above 20% or below −45% (Extended Data Fig. 10). The ΔBMI % estimates were set to missing for participants who did not pass quality control.
To enable genetic associations to be interpreted in units of weight rather than ΔBMI % , we also defined a corresponding Δweight phenotype, defined as the change in weight from baseline in kilograms. We note that, because adult height is treated as constant during the treatment window, the percentage change in BMI (ΔBMI % ) is mathematically identical to the percentage change in weight (Δweight % ).
For the side effect phenotypes, we defined separate case–control phenotypes for each side effect recorded in the survey, contrasting those who self-rated their side effects as moderate or severe (cases) to those who self-rated their side effects as mild or non-existent (controls). As before, for study participants who reported taking more than one GLP1 medication, we selected the GLP1 medication that they reported taking for the longest period of time.
We further defined phenotypes to represent covariates, specifically for drug type (semaglutide = 1 versus tirzepatide = 0), dosage and days on treatment. For the dosage phenotype, we used the reported most recent weekly dosage in milligrams; this was either the final dose or the current dose for people still taking medication.
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