The role of genetic variation of human metabolism for BMI, mental traits and mental disorders

Hebebrand, J., Peters, T., Schijven, D., Hebebrand, M., Grasemann, C., Winkler, T. W., Heid, I. M., Antel, J., Föcker, M., Tegeler, L., Brauner, L., Adan, R. A., Luykx, J. J., Correll, C. U., König, I. R., Hinney, A., & Libuda, L. (2018). The role of genetic variation of human metabolism for BMI, mental traits and mental disorders. Molecular Metabolism, 12, 1-11. doi:10.1016/j.molmet.2018.03.015.
The aim was to assess whether loci associated with metabolic traits also have a significant role in BMI and mental traits/disorders
We first assessed the number of single nucleotide polymorphisms (SNPs) with genome-wide significance for human metabolism (NHGRI-EBI Catalog). These 516 SNPs (216 independent loci) were looked-up in genome-wide association studies for association with body mass index (BMI) and the mental traits/disorders educational attainment, neuroticism, schizophrenia, well-being, anxiety, depressive symptoms, major depressive disorder, autism-spectrum disorder, attention-deficit/hyperactivity disorder, Alzheimer's disease, bipolar disorder, aggressive behavior, and internalizing problems. A strict significance threshold of p < 6.92 × 10−6 was based on the correction for 516 SNPs and all 14 phenotypes, a second less conservative threshold (p < 9.69 × 10−5) on the correction for the 516 SNPs only.
19 SNPs located in nine independent loci revealed p-values < 6.92 × 10−6; the less strict criterion was met by 41 SNPs in 24 independent loci. BMI and schizophrenia showed the most pronounced genetic overlap with human metabolism with three loci each meeting the strict significance threshold. Overall, genetic variation associated with estimated glomerular filtration rate showed up frequently; single metabolite SNPs were associated with more than one phenotype. Replications in independent samples were obtained for BMI and educational attainment.
Approximately 5–10% of the regions involved in the regulation of blood/urine metabolite levels seem to also play a role in BMI and mental traits/disorders and related phenotypes. If validated in metabolomic studies of the respective phenotypes, the associated blood/urine metabolites may enable novel preventive and therapeutic strategies.
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