title: TNF receptors 1 and 2 exert distinct region-specific effects on striatal and hippocampal grey matter volumes (VBM) in healthy adults.
abstract: Tumour necrosis factor alpha (TNFα) has been implicated in the pathophysiology of neurodegenerative and neuropsychiatric disease, with research highlighting a role for TNFα in hippocampal and striatal regulation. TNFα signals are primarily transduced by TNF receptors 1 and 2 (TNFR1 and TNFR2), encoded by TNFRSF1A and TNFRSF1B, which exert opposing effects on cell survival (TNFR1, neurodegenerative; TNFR2, neuroprotective). We therefore sought to explore the respective roles of TNFR1 and TNFR2 in the regulation of hippocampal and striatal morphology in an imaging genetics study. Voxel-based morphometry was used to analyse the associations between TNFRSF1A (rs4149576 and rs4149577) and TNFRSF1B (rs1061624) genotypes and grey matter structure. The final samples comprised a total of 505 subjects (mean age = 33.29, SD = 11.55 years; 285 females and 220 males) for morphometric analyses of rs1061624 and rs4149576, and 493 subjects for rs4149577 (mean age = 33.20, SD = 11.56 years; 281 females and 212 males). Analyses of TNFRSF1A single nucleotide polymorphisms (SNPs) rs4149576 and rs4149577 showed highly significant genotypic associations with striatal volume but not the hippocampus. Specifically, for rs4149576, G homozygotes were associated with reduced caudate nucleus volumes relative to A homozygotes and heterozygotes, whereas for rs4149577, reduced caudate volumes were observed in C homozygotes relative to T homozygotes and heterozygotes. Analysis of the TNFRSF1B SNP rs1061624 yielded a significant association with hippocampal but not with striatal volume, whereby G homozygotes were associated with increased volumes relative to A homozygotes and heterozygotes. Our findings indicate a role for TNFR1 in regulating striatal but not hippocampal morphology, as well as a complementary role for TNFR2 in hippocampal but not in striatal morphology.
authors.affiliation: Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Stacey
authors.affiliation: Department of Psychiatry, University of Münster, Münster.
authors.forename: R
authors.initials: R
authors.lastname: Redlich
authors.affiliation: Department of Psychiatry, University of Münster, Münster.
authors.forename: A
authors.initials: A
authors.lastname: Büschel
authors.affiliation: Department of Psychiatry, University of Münster, Münster.
authors.forename: N
authors.initials: N
authors.lastname: Opel
authors.affiliation: Department of Psychiatry, University of Münster, Münster.
authors.forename: D
authors.initials: D
authors.lastname: Grotegerd
authors.affiliation: Department of Psychiatry, University of Münster, Münster.
authors.forename: D
authors.initials: D
authors.lastname: Zaremba
authors.affiliation: Department of Psychiatry, University of Münster, Münster.
authors.forename: K
authors.initials: K
authors.lastname: Dohm
authors.affiliation: Department of Psychiatry, University of Münster, Münster.
authors.forename: C
authors.initials: C
authors.lastname: Bürger
authors.affiliation: Department of Psychiatry, University of Münster, Münster.
authors.forename: S L
authors.initials: SL
authors.lastname: Meinert
authors.affiliation: Department of Psychiatry, University of Münster, Münster.
authors.forename: K
authors.initials: K
authors.lastname: Förster
authors.affiliation: Department of Psychiatry, University of Münster, Münster.
authors.forename: J
authors.initials: J
authors.lastname: Repple
authors.affiliation: Department of Psychiatry, University of Münster, Münster.
authors.forename: C
authors.initials: C
authors.lastname: Kaufmann
authors.affiliation: Department of Clinical Radiology, University of Münster, Münster.
authors.forename: H
authors.initials: H
authors.lastname: Kugel
authors.affiliation: Department of Clinical Radiology, University of Münster, Münster.
authors.forename: W
authors.initials: W
authors.lastname: Heindel
authors.affiliation: Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: V
authors.initials: V
authors.lastname: Arolt
authors.affiliation: Department of Psychiatry, University of Münster, Münster.|Department of Psychiatry, University of Marburg, Marburg, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Dannlowski
authors.affiliation: Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: B T
authors.initials: BT
authors.lastname: Baune
mesh_terms: D000328:Adult; D003342:Corpus Striatum / Q000378:metabolism / Q000502:physiology*; D005260:Female; D066128:Gray Matter / Q000378:metabolism / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008297:Male; D017072:Neostriatum / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics* / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C439524:TNF protein, human; C506235:TNFRSF1A protein, human; C415902:TNFRSF1B protein, human; D014409:Tumor Necrosis Factor-alpha
keywords: Hippocampus; TNF receptor; imaging genetics; neuroinflammation; striatum