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Cited by 37Genetic Associations and EpidemiologyTreatment of Major DepressionNeurotransmitter Receptor Influence on Behavior

A rare missense variant in RCL1 segregates with depression in extended families.

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Amin, N, de Vrij, F M S, Baghdadi, M, Brouwer, R W W, van Rooij, J G J, Jovanova, O, Uitterlinden, A G, Hofman, A +10 more·2018·Molecular Psychiatry
DOI 10.1038/mp.2017.49PMC PMC5984098
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Abstract

Depression is the most prevalent psychiatric disorder with a complex and elusive etiology that is moderately heritable. Identification of genes would greatly facilitate the elucidation of the biological mechanisms underlying depression, however, its complex etiology has proved to be a major bottleneck in the identification of its genetic risk factors, especially in genome-wide association-like studies. In this study, we exploit the properties of a genetic isolate and its family-based structure to explore whether relatively rare exonic variants influence the burden of depressive symptoms in families. Using a multistep approach involving linkage and haplotype analyses followed by exome sequencing in the Erasmus Rucphen Family (ERF) study, we identified a rare (minor allele frequency (MAF)=1%) missense c.1114C>T mutation (rs115482041) in the RCL1 gene segregating with depression across multiple generations. Rs115482041 showed significant association with depressive symptoms ( N =2393, β T-allele =2.33, P -value=1 × 10 −4 ) and explained 2.9% of the estimated genetic variance of depressive symptoms (22%) in ERF. Despite being twice as rare (MAF<0.5%), c.1114C>T showed similar effect and significant association with depressive symptoms in samples from the independent population-based Rotterdam study ( N =1604, β T-allele =3.60, P -value=3 × 10 − 2 ). A comparison of RCL1 expression in human and mouse brain revealed a striking co-localization of RCL1 with the layer 1 interlaminar subclass of astrocytes found exclusively in higher-order primates. Our findings identify RCL1 as a novel candidate gene for depression and offer insights into mechanisms through which RCL1 may be relevant for depression.

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  • In postmortem brains, RCL1 is expressed specifically in the nuclear region of neurons and in the long processes of ILAs (and in no other protoplasmic astrocytes).

    “In postmortem brains, RCL1 is expressed specifically in the nuclear region of neurons and in the long processes of ILAs (and in no other protoplasmic astrocytes), leading to the hypothesis of an active role of ILAs in depression.”

    From Interlaminar and varicose-projection astrocytes: toward a new understanding of the primate brain (2024) · cites this paper as Amin et al., 2018

    The Results section reports nuclear RCL1 labeling in human postmortem cortex, including neurons, and abundant labeling in the long processes of interlaminar astrocytes. It reports an absence of cytoplasmic labeling in GFAP-positive astrocytes in cortical layers 5/6, but does not establish the broader claim that no other protoplasmic astrocytes express RCL1. The Discussion treats a role for interlaminar astrocytes in depression as a possibility requiring further study. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Amin et al. (2018) suggests a direct involvement of ILAs in patients with depressive symptoms.

    “On the other hand, another study by Amin et al. (2018) on depression, suggests a direct involvement of ILAs in patients with depressive symptoms.”

    From Interlaminar and varicose-projection astrocytes: toward a new understanding of the primate brain (2024) · cites this paper as Amin et al. (2018)

    The Discussion reports abundant RCL1 labeling in interlaminar astrocytes in the human cortex and raises their possible role in depression. It does not establish their direct involvement in patients with depressive symptoms: the authors say they cannot distinguish neuronal from astrocyte contributions and call for further study. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The RCL1 expression pattern leads to the hypothesis of an active role of ILAs in depression.

    “In postmortem brains, RCL1 is expressed specifically in the nuclear region of neurons and in the long processes of ILAs (and in no other protoplasmic astrocytes), leading to the hypothesis of an active role of ILAs in depression.”

    From Interlaminar and varicose-projection astrocytes: toward a new understanding of the primate brain (2024) · cites this paper as Amin et al., 2018

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Authors
Amin, N., de Vrij, F. M. S., Baghdadi, M., Brouwer, R. W. W., van Rooij, J. G. J., Jovanova, O., Uitterlinden, A. G., Hofman, A., Janssen, H. L. A., Darwish Murad, S., Kraaij, R., Stedehouder, J., van den Hout, M. C. G. N., Kros, J. M., van IJcken, W. F. J., Tiemeier, H., Kushner, S. A., & van Duijn, C. M.
Affiliations
  • Erasmus MC (NL)
  • University Health Network (CA)
Corresponding author
Amin, N
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2017-03-21
Volume
23
Issue
5
Pages
1120-1126
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/mp.2017.49
PMC
PMC5984098
OpenAlex
W2597448237
Cited by
37
References
5
Citations by year
2025: 3 · 2024: 3 · 2023: 1 · 2022: 6 · 2021: 6 · 2020: 5 · 2019: 8 · 2018: 4 · 2017: 1
FWCI
3.27
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
Funders
  • European Commission (QLG2-CT-2002-01254, 018947, LSHG-CT-2006-01947, 2007–2013, FP7 2007-2013, 201413, FP7/2007, 01254)
  • ZonMw (91111025, Project 91111025, 050-060-810)
  • Russian Foundation for Basic Research (HEALTH-F4-2007-201413, 047.017.043, NWORFBR 047.017.043)
  • Erasmus Medisch Centrum (050-060-810)
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (050.060.810, FP7 2007-2013, NWO-RFBR 047.017.043, 047.017.043)
  • Hersenstichting (F2012(1)-39)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
depression, missense mutations, rare variants, genetic risk factors, genetic isolate, linkage analysis, haplotype analysis, exome sequencing, genetic variance, astrocytes, brain expression, candidate genes
MeSH terms
Exome Sequencing, Adult, Aged, Alleles, Animals, Depression, Depressive Disorder, Exons, Family, Female, Gene Frequency, Haplotypes, Humans, Genetic Linkage, Male, Middle Aged, Mutation, Pedigree, Risk Factors, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Mice, Genome-Wide Association Study, Exome

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