Assessing the genetic overlap between BMI and cognitive function

Abstract

Obesity and low cognitive function are associated with multiple adverse health outcomes across the life course. They have a small phenotypic correlation (r=−0.11; high body mass index (BMI)−low cognitive function), but whether they have a shared genetic aetiology is unknown. We investigated the phenotypic and genetic correlations between the traits using data from 6815 unrelated, genotyped members of Generation Scotland, an ethnically homogeneous cohort from five sites across Scotland. Genetic correlations were estimated using the following: same-sample bivariate genome-wide complex trait analysis (GCTA)–GREML; independent samples bivariate GCTA–GREML using Generation Scotland for cognitive data and four other samples (n=20 806) for BMI; and bivariate LDSC analysis using the largest genome-wide association study (GWAS) summary data on cognitive function (n=48 462) and BMI (n=339 224) to date. The GWAS summary data were also used to create polygenic scores for the two traits, with within- and cross-trait prediction taking place in the independent Generation Scotland cohort. A large genetic correlation of −0.51 (s.e. 0.15) was observed using the same-sample GCTA–GREML approach compared with −0.10 (s.e. 0.08) from the independent-samples GCTA–GREML approach and −0.22 (s.e. 0.03) from the bivariate LDSC analysis. A genetic profile score using cognition-specific genetic variants accounts for 0.08% (P=0.020) of the variance in BMI and a genetic profile score using BMI-specific variants accounts for 0.42% (P=1.9 × 10−7) of the variance in cognitive function. Seven common genetic variants are significantly associated with both traits at P<5 × 10−5, which is significantly more than expected by chance (P=0.007). All these results suggest there are shared genetic contributions to BMI and cognitive function.

Neurobehavioural Correlates of Obesity are Largely Heritable

“…This is in accordance with recent molecular genetics evidence that 75% of obesity related genes express preferentially in the brain (4). Similarly, the genetic correlation between cognition and BMI uncovered in our sample is at the same magnitude as molecular estimates of associations between more specific cognitive measures and BMI (15,18). The current evidence further supports the brain-gene association with obesity vulnerability.…”

“…Similarly to other recent papers, (20,27), we used the weights of each individual feature within a neurobehavioural factor (personality test, cognitive test, brain parcel) to create an aggregate BMI risk score or poly-phenotype score (PPS). This is similar to the polygenic score approach in genetics, where the small effects of several polymorphisms are aggregated to yield a total effect score (15,19,20,27). We used the correlation values as weights to multiply each participant's scaled measurements, and aggregated the results into a single composite variable, the PPS.…”

“…The main goal was to assess whether the aforementioned obesity-neurobehavioural associations are of genetic or environmental origin. Recent evidence from behavioural and molecular genetics suggests that there is considerable genetic overlap between obesity, cognitive test scores, and brain imaging findings (15)(16)(17)(18)(19)(20). However, the evidence so far is not comprehensive across all neurobehavioural factors discussed.…”

Mapping heritability of obesity by brain cell types

“…3b; Supplementary Table 5). Sixteen of the 22 cell types were also enriched "intelligence" and "worry", two traits genetically anticorrelated with obesity (overlapping sets of associated loci with opposite effect sizes) 27,28 ( Supplementary Table 7).…”

Body Mass Index Is Related to Cognitive Function in Chinese Older Adults: So What?

“…However, a direct causality from high BMI to impaired CF has not been supported by genetic studies, as indicated by findings of seven common genetic variants for both traits and a large genetic correlation (r=-0.51); [16]. With such a strong genetic predisposition for both BMI and impaired CF, the relation of BMI to CF might have been misconceptualized as causal and thus difficult to be consistent in the findings.…”