Contribution of Rare and Potentially Functionally Relevant Sequence Variants in Schizophrenia Risk-Locus Xq28,distal

I Claus¹, S Sivalingam^{2

3

4

5}, A C Koller¹, A Weiß¹, C M Mathey¹, L Sindermann¹, D Klein¹, L Henschel^{1

6}, K U Ludwig¹, P Hoffmann^{1

7

8}, A Heimbach⁹, S Heilmann-Heimbach¹, H Vedder¹⁰, J Kammerer-Ciernioch¹⁰, T Stürmer¹¹, F Streit¹², A Maaser-Hecker^{1

13

14

15}, I Nenadić^{16

17

18}, B T Baune^{19

20

21}, A M Hartmann²², B Konte²², I Giegling²², U Heilbronner²³, M Wagner²⁴, A Philipsen²⁴, B Schmidt²⁵, D Rujescu²², A Buness^{2

3

4}, T G Schulze^{23

26}, M Rietschel¹², A J Forstner^{1

27}, M M Nöthen¹, F Degenhardt^{1

28}

Affiliations

¹ Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany.
² Institute for Medical Biometry, Informatics and Epidemiology, Medical Faculty, University of Bonn, Bonn, Germany.
³ Institute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, Bonn, Germany.
⁴ Core Unit for Bioinformatics Data Analysis, Medical Faculty, University of Bonn, Bonn, Germany.
⁵ Institute of Human Genetics, Medical Faculty, University Hospital of Düsseldorf, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.
⁶ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
⁷ Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
⁸ Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland.
⁹ NGS Core Facility, Medical Faculty, University of Bonn, Bonn, Germany.
¹⁰ Psychiatric Center Nordbaden, Wiesloch, Germany.
¹¹ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, USA.
¹² Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
¹³ Genetics and Aging Research Unit, Department of Neurology, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
¹⁴ Harvard Medical School, Boston, Massachusetts, USA.
¹⁵ McCance Center for Brain Health, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹⁶ Department of Psychiatry und Psychotherapy, University of Marburg, Marburg, Germany.
¹⁷ Center for Mind, Brain and Behavior (CMBB), University of Marburg, Marburg, Germany.
¹⁸ Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.
¹⁹ Department of Psychiatry, University of Münster, Münster, Germany.
²⁰ Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Central Melbourne, Australia.
²¹ The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Central Melbourne, Australia.
²² Department of Psychiatry and Psychotherapy, Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Vienna, Austria.
²³ Institute of Psychiatric Phenomics and Genomics (IPPG), LMU University Hospital, LMU Munich, Munich, Germany.
²⁴ Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
²⁵ Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University Hospital Essen, University Duisburg-Essen, Essen, Germany.
²⁶ Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, New York, USA.
²⁷ Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany.
²⁸ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

PMID: 39473393
DOI: 10.1002/ajmg.b.33011

Contribution of Rare and Potentially Functionally Relevant Sequence Variants in Schizophrenia Risk-Locus Xq28,distal

I Claus et al. Am J Med Genet B Neuropsychiatr Genet. 2025 Apr.

. 2025 Apr;198(3):e33011.

doi: 10.1002/ajmg.b.33011. Epub 2024 Oct 30.

Authors

Affiliations

¹ Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, Germany.
² Institute for Medical Biometry, Informatics and Epidemiology, Medical Faculty, University of Bonn, Bonn, Germany.
³ Institute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, Bonn, Germany.
⁴ Core Unit for Bioinformatics Data Analysis, Medical Faculty, University of Bonn, Bonn, Germany.
⁵ Institute of Human Genetics, Medical Faculty, University Hospital of Düsseldorf, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.
⁶ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
⁷ Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
⁸ Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, Basel, Switzerland.
⁹ NGS Core Facility, Medical Faculty, University of Bonn, Bonn, Germany.
¹⁰ Psychiatric Center Nordbaden, Wiesloch, Germany.
¹¹ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, USA.
¹² Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
¹³ Genetics and Aging Research Unit, Department of Neurology, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
¹⁴ Harvard Medical School, Boston, Massachusetts, USA.
¹⁵ McCance Center for Brain Health, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹⁶ Department of Psychiatry und Psychotherapy, University of Marburg, Marburg, Germany.
¹⁷ Center for Mind, Brain and Behavior (CMBB), University of Marburg, Marburg, Germany.
¹⁸ Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.
¹⁹ Department of Psychiatry, University of Münster, Münster, Germany.
²⁰ Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Central Melbourne, Australia.
²¹ The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Central Melbourne, Australia.
²² Department of Psychiatry and Psychotherapy, Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Vienna, Austria.
²³ Institute of Psychiatric Phenomics and Genomics (IPPG), LMU University Hospital, LMU Munich, Munich, Germany.
²⁴ Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany.
²⁵ Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University Hospital Essen, University Duisburg-Essen, Essen, Germany.
²⁶ Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, New York, USA.
²⁷ Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany.
²⁸ Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

PMID: 39473393
DOI: 10.1002/ajmg.b.33011

Abstract

Duplications of the Xq28,distal locus have been described in male and female patients with schizophrenia (SCZ) or intellectual disability. The Xq28,distal locus spans eight protein-coding genes (F8, CMC4, MTCP1, BRCC3, VBP1, FUNDC2, CLIC2, and RAB39B) and is flanked by recurrent genomic breakpoints. Thus, the issue of which gene/s at this locus is/are relevant in terms of SCZ pathogenesis remains unclear. The aim of this study was to investigate the contribution of rare and potentially functionally relevant sequence variants within the Xq28,distal locus to SCZ risk using the single-molecule molecular inversion probes (smMIP) method. Targeted sequencing was performed in a cohort of 1935 patients with SCZ and 1905 controls of European ancestry. The consecutive statistical analysis addressed two main areas. On the level of the individual variants, allele counts in the patient and control cohort were systematically compared with a Fisher's exact test: (i) for the entire present study cohort; (ii) for patients and controls separated by sex; and (iii) in combination with data published by the Schizophrenia Exome Meta-Analysis (SCHEMA) consortium. On the gene-wise level, a burden analysis was performed using the X-chromosomal model of the Optimal Unified Sequence Kernel Association Test (SKAT-O), with adjustment for possible sex-specific effects. Targeted sequencing identified a total of 13 rare and potentially functional variants in four patients and 11 controls. However, neither at the level of individual rare and potentially functional variants nor at the level of the eight protein-coding genes at the Xq28,distal locus was a statistically significant enrichment in patients compared to controls observed. Although inconclusive, the present findings represent a step toward improved understanding of the contribution of X-chromosomal risk factors in neuropsychiatric disorder development, which is an underrepresented aspect of genetic studies in this field.

Keywords: X‐chromosome; burden analysis; copy number variation; rare variants; schizophrenia.

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References

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Contribution of Rare and Potentially Functionally Relevant Sequence Variants in Schizophrenia Risk-Locus Xq28,distal

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Contribution of Rare and Potentially Functionally Relevant Sequence Variants in Schizophrenia Risk-Locus Xq28,distal

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