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

Johannes Hebebrand; Triinu Peters; Dick Schijven; Moritz Hebebrand; Corinna Grasemann; Thomas W Winkler; Iris M Heid; Jochen Antel; Manuel Föcker; Lisa Tegeler; Lena Brauner; Roger A H Adan; Jurjen J Luykx; Christoph U Correll; Inke R König; Anke Hinney; Lars Libuda

doi:10.1016/j.molmet.2018.03.015

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

Mol Metab. 2018 Jun:12:1-11. doi: 10.1016/j.molmet.2018.03.015. Epub 2018 Apr 3.

Authors

Johannes Hebebrand¹, Triinu Peters¹, Dick Schijven², Moritz Hebebrand¹, Corinna Grasemann³, Thomas W Winkler⁴, Iris M Heid⁴, Jochen Antel¹, Manuel Föcker¹, Lisa Tegeler¹, Lena Brauner¹, Roger A H Adan⁵, Jurjen J Luykx⁶, Christoph U Correll⁷, Inke R König⁸, Anke Hinney¹, Lars Libuda⁹

Affiliations

¹ Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
² Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
³ Pediatric Endocrinology and Diabetology, Klinik für Kinderheilkunde II, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
⁴ Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany.
⁵ Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
⁶ Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Psychiatry, ZNA Hospitals, Antwerp, Belgium.
⁷ Division of Psychiatry Research, Northwell Health, The Zucker Hillside Hospital, Glen Oaks, NY, USA.
⁸ Institute of Medical Biometry and Statistics, University of Luebeck, Luebeck, Schleswig-Holstein, Germany.
⁹ Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. Electronic address: lars.libuda@uni-due.de.

Abstract

Objective: The aim was to assess whether loci associated with metabolic traits also have a significant role in BMI and mental traits/disorders METHODS: 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.

Results: 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.

Conclusions: 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.

Keywords: Cross-trait analysis; Educational attainment; Intelligence; Metabolites; Obesity; Schizophrenia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Body Mass Index*
Humans
Intelligence / genetics
Mental Disorders / genetics*
Metabolome / genetics*
Polymorphism, Single Nucleotide*