Do genetic risk scores for body mass index predict risk of phobic anxiety? Evidence for a shared genetic risk factor

Abstract

Background Obesity and anxiety are often linked but the direction of effects is not clear. Methods Using genetic instrumental variable (IV) analyses in a sample of 5911 female participants from the Nurses´ Health Study (NHS, initiated in 1976) and 3697 male participants from the Health Professional Follow-up Study (HPFS, initiated in 1986), we aim to determine whether obesity increases symptoms of phobic anxiety. FTO, MC4R, and a genetic risk score (GRS) based on 32 single nucleotide polymorphisms that significantly predict body mass index (BMI), were used as instrumental variables. “Functional” GRS corresponding with specific biological pathways that shape BMI (adipogenesis, appetite, and cardio-pulmonary), were considered. Phobic anxiety as measured by the Crown Crisp Experimental Index (CCI) in 2004 in NHS and 2000 in HPFS was the main outcome. Results In observational analysis, a one unit higher BMI was associated with higher phobic anxiety symptoms (women NHS: beta=0.05; 95% Confidence Interval (CI): 0.030 – 0.068 and men, HPFS, beta = 0.04; 95% CI: 0.016 – 0.071). IV analyses showed that BMI instrumented by FTO was associated with higher phobic anxiety symptoms (p = 0.005) but BMI instrumented by GRS was not (p=0.256). Functional GRS scores showed heterogeneous, non-significant effects of BMI on phobic anxiety symptoms. Conclusions Our findings do not provide conclusive evidence in favor of the hypothesis that higher BMI leads to higher levels of phobic anxiety, but rather suggest that genes that influence obesity, in particular FTO, may have direct effects on phobic anxiety, i.e., that obesity and phobic anxiety may share common genetic determinants.

Searching for the causal effects of body mass index in over 300 000 participants in UK Biobank, using Mendelian randomization

“…The prevalence of anxiety has been shown to be higher in obese compared with non-obese people [39–44] and higher in both underweight and overweight/obese people compared with those of normal weight [45]. The few instrumental variable studies estimating the causal effect of BMI on anxiety that have been performed to date (one specifically looking at phobic anxiety [46] and the other using an anxiety measure defined using the Hospital Anxiety and Depression Scale [HADS] 50 ), did not find evidence of a causal effect, although this may be due to insufficient statistical power [46,47]. Some previous MR studies using a BMI genetic risk score provided evidence that an increase in BMI adversely affects risk of depression symptoms [48] and major depressive disorder [49] while others found little evidence [50,51].…”

Telomere length and health outcomes: A two-sample genetic instrumental variables analysis

“…Educational attainment was constructed as a categorical variable with four levels: less than high school education (reference group), high school or GED completed, some college, and college completed. We also account for residual population stratification by including the first four genetic principal components-derived eigenvectors, a technique used in prior work (Chang and others 2014; Walter and others 2015). …”

Searching for the causal effects of BMI in over 300 000 individuals, using Mendelian randomization

“…The prevalence of anxiety has been shown to be higher in obese compared with non-obese people 43–47 , although Vainik et al found no correlation between BMI and neuroticism 48 . The few instrumental variable studies estimating the causal effect of BMI on anxiety that have been performed to date (one specifically looking at phobic anxiety 49 and the other using an anxiety measure defined using the Hospital Anxiety and Depression Scale (HADS) 50 ), did not find evidence of a causal effect, although this may be due to insufficient statistical power 49,50 . Two recent MR studies provided evidence that an increase in BMI adversely affects risk of depression symptoms 51 and major depressive disorder 52 .…”