Genome-wide mapping of genetic determinants influencing DNA methylation and gene expression in human hippocampus

Herbert Schulz; Ann-Kathrin Ruppert; Stefan Herms; Christiane Wolf; Nazanin Mirza-Schreiber; Oliver Stegle; Darina Czamara; Andreas J Forstner; Sugirthan Sivalingam; Susanne Schoch; Susanne Moebus; Benno Pütz; Axel Hillmer; Nadine Fricker; Hartmut Vatter; Bertram Müller-Myhsok; Markus M Nöthen; Albert J Becker; Per Hoffmann; Thomas Sander; Sven Cichon

doi:10.1038/s41467-017-01818-4

Genome-wide mapping of genetic determinants influencing DNA methylation and gene expression in human hippocampus

Nat Commun. 2017 Nov 15;8(1):1511. doi: 10.1038/s41467-017-01818-4.

Authors

Herbert Schulz¹, Ann-Kathrin Ruppert¹, Stefan Herms^{2

3

4}, Christiane Wolf^{5

6

7}, Nazanin Mirza-Schreiber⁵, Oliver Stegle⁶, Darina Czamara⁵, Andreas J Forstner^{2

3

8}, Sugirthan Sivalingam², Susanne Schoch^{9

10}, Susanne Moebus¹¹, Benno Pütz⁵, Axel Hillmer^{12

13}, Nadine Fricker², Hartmut Vatter¹⁴, Bertram Müller-Myhsok^{5

15

16}, Markus M Nöthen², Albert J Becker⁹, Per Hoffmann^{2

3

4

17}, Thomas Sander¹⁸, Sven Cichon^{19

20

21

22}

Affiliations

¹ Cologne Center for Genomics, University of Cologne, 50931, Cologne, Germany.
² Department of Genomics, Life & Brain Center, Institute of Human Genetics, University of Bonn, 53127, Bonn, Germany.
³ Department of Biomedicine, University of Basel, 4031, Basel, Switzerland.
⁴ Institute of Medical Genetics and Pathology, University Hospital Basel, 4031, Basel, Switzerland.
⁵ Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804, Munich, Germany.
⁶ European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, CB10 1SD, Cambridge, UK.
⁷ Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, 97080, Würzburg, Germany.
⁸ Department of Psychiatry (UPK), University of Basel, 4012, Basel, Switzerland.
⁹ Department of Neuropathology, University of Bonn Medical Center, 53127, Bonn, Germany.
¹⁰ Department of Epileptology, University of Bonn Medical Center, 53105, Bonn, Germany.
¹¹ Institute of Medical Informatics, Biometry and Epidemiology, University Duisburg-Essen, 45147, Essen, Germany.
¹² Genome Institute of Singapore, Singapore, 138672, Singapore.
¹³ TRON-Translational Oncology at the University Medical Center of the Johannes Gutenberg University gGmbH, 55131, Mainz, Germany.
¹⁴ Department of Neurosurgery, University of Bonn Medical Center, 53127, Bonn, Germany.
¹⁵ Munich Cluster for Systems Neurology (SyNergy), 81377, Munich, Germany.
¹⁶ Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3BX, UK.
¹⁷ Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, 52425, Jülich, Germany.
¹⁸ Cologne Center for Genomics, University of Cologne, 50931, Cologne, Germany. sandert@uni-koeln.de.
¹⁹ Department of Genomics, Life & Brain Center, Institute of Human Genetics, University of Bonn, 53127, Bonn, Germany. sven.cichon@unibas.ch.
²⁰ Department of Biomedicine, University of Basel, 4031, Basel, Switzerland. sven.cichon@unibas.ch.
²¹ Institute of Medical Genetics and Pathology, University Hospital Basel, 4031, Basel, Switzerland. sven.cichon@unibas.ch.
²² Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, 52425, Jülich, Germany. sven.cichon@unibas.ch.

Abstract

Emerging evidence emphasizes the strong impact of regulatory genomic elements in neurodevelopmental processes and the complex pathways of brain disorders. The present genome-wide quantitative trait loci analyses explore the cis-regulatory effects of single-nucleotide polymorphisms (SNPs) on DNA methylation (meQTL) and gene expression (eQTL) in 110 human hippocampal biopsies. We identify cis-meQTLs at 14,118 CpG methylation sites and cis-eQTLs for 302 3'-mRNA transcripts of 288 genes. Hippocampal cis-meQTL-CpGs are enriched in flanking regions of active promoters, CpG island shores, binding sites of the transcription factor CTCF and brain eQTLs. Cis-acting SNPs of hippocampal meQTLs and eQTLs significantly overlap schizophrenia-associated SNPs. Correlations of CpG methylation and RNA expression are found for 34 genes. Our comprehensive maps of cis-acting hippocampal meQTLs and eQTLs provide a link between disease-associated SNPs and the regulatory genome that will improve the functional interpretation of non-coding genetic variants in the molecular genetic dissection of brain disorders.

Publication types

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

MeSH terms

Adolescent
Adult
Aged
Child
Child, Preschool
DNA Methylation*
Epilepsy, Temporal Lobe / genetics*
Female
Gene Expression Profiling*
Genome-Wide Association Study / methods*
Hippocampus / metabolism*
Humans
Infant
Male
Middle Aged
Polymorphism, Single Nucleotide
Quantitative Trait Loci / genetics
Young Adult