Multi-ancestry phenome-wide association of complement component 4 variation with psychiatric and brain phenotypes in youth

被引：7

作者：

Hernandez, Leanna M. M. ^{[1
]}

Kim, Minsoo ^{[1
,2
,3
]}

Zhang, Pan ^{[1
]}

Bethlehem, Richard A. I. ^{[4
]}

Hoftman, Gil ^{[1
]}

Loughnan, Robert ^{[5
]}

Smith, Diana ^{[5
]}

Bookheimer, Susan Y. ^{[1
]}

Fan, Chun Chieh ^{[5
]}

Bearden, Carrie E. E. ^{[1
]}

Thompson, Wesley K. K. ^{[5
]}

Gandal, Michael J. J. ^{[1
,2
,6
,7
,8
,9
]}

机构：

[1] Univ Calif Los Angeles, Semel Inst, David Geffen Sch Med, Dept Psychiat, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, Semel Inst, David Geffen Sch Med, Program Neurobehav Genet, Los Angeles, CA 90095 USA

[4] Univ Cambridge, Dept Psychiat, Cambridge Biomed Campus, Cambridge CB2 0SZ, England

[5] Univ Calif San Diego, Populat Neurosci & Genet Lab, San Diego, CA 92093 USA

[6] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA USA

[7] Penn Med, Lifespan Brain Inst, Philadelphia, PA 19104 USA

[8] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA

[9] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA USA

来源：

GENOME BIOLOGY | 2023年 / 24卷 / 01期

关键词：

Schizophrenia; Psychosis; Neuroimaging; Genetics; Gene expression; Complement; Brain; MEDIAL TEMPORAL-LOBE; ENTORHINAL CORTEX; PROGRESSIVE REDUCTION; GENOTYPE IMPUTATION; PSYCHOTIC DISORDERS; CORTICAL THICKNESS; SCHIZOPHRENIA RISK; CEREBRAL-CORTEX; CYTOARCHITECTURE; VOLUME;

D O I：

10.1186/s13059-023-02878-0

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

BackgroundIncreased expression of the complement component 4A (C4A) gene is associated with a greater lifetime risk of schizophrenia. In the brain, C4A is involved in synaptic pruning; yet, it remains unclear the extent to which upregulation of C4A alters brain development or is associated with the risk for psychotic symptoms in childhood. Here, we perform a multi-ancestry phenome-wide association study in 7789 children aged 9-12 years to examine the relationship between genetically regulated expression (GREx) of C4A, childhood brain structure, cognition, and psychiatric symptoms.ResultsWhile C4A GREx is not related to childhood psychotic experiences, cognition, or global measures of brain structure, it is associated with a localized reduction in regional surface area (SA) of the entorhinal cortex. Furthermore, we show that reduced entorhinal cortex SA at 9-10 years predicts a greater number and severity of psychosis-like events at 1-year and 2-year follow-up time points. We also demonstrate that the effects of C4A on the entorhinal cortex are independent of genome-wide polygenic risk for schizophrenia.ConclusionsOur results suggest neurodevelopmental effects of C4A on childhood medial temporal lobe structure, which may serve as a biomarker for schizophrenia risk prior to symptom onset.

引用

页数：19

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