Developing a Polygenic Risk Score for Weight Gain in People Treated for Psychosis-Application in a Real-World Setting

Genetic factors are thought to play an important role in antipsychotic-induced weight gain (AIWG). Polygenic risk scores (PRS) could provide a measure of genetic predisposition to antipsychotic drug induced weight gain (AIWG).We conducted a study to examine how a PRS, generated using SNPs, identified from a recent meta-analysis, related to weight-change over time in people with first episode-psychosis.

The PRS included SNPs in six different genes, identified as having significant associations (p < 0.05) with AIWG. These were HTR2C rs3813929; MTHFR rs1801133; ADRA2A rs1800544; MC4R rs489693; LEPR rs1137101 and CNR1 rs1049353. An additive PRS and a risk allele based weighted PRS were created based on risk allele counts and presence or absence of risk alleles respectively. The additive PRS was also used to create low/high genetic risk groups for analysis. The association between PRS and weight gain per day (WGPD) in grams/day as well as BMI percentage change (=> 7%) was investigated using regression models.

In multiple regression analysis, the additive PRS significantly predicted AIWG in females (adjusted r² = 0.59, B: unstandardised regression coefficient = 24.4 g/day p < 0.05), but not in males. ANCOVA showed that high genetic risk groups had greater WGPD (p = 0.018), with significant PRS gender interactions driven by markedly higher WGPD in high-risk females (p = 0.039). None of the models tested were associated with BMI percentage change.

We report a PRS that is predictive of weight gain in women treated for first episode psychosis, accounting for 59% of the variance daily weight-gain over time. Validation in an independent cohort is required, as is determining whether it is feasible to apply the PRS prospectively.