Case-control association study of the close homologue of L1 (CHL1) gene and schizophrenia in the Chinese population

doi:10.1016/j.schres.2004.06.001

Schizophrenia Research

Volume 73, Issues 2–3, 1 March 2005, Pages 269-274

https://doi.org/10.1016/j.schres.2004.06.001 Get rights and content

Abstract

The close homolog of L1 (CHL1), located on human chromosome 3p26.1, is a newly identified member of the L1 family of cell adhesion molecules which play important roles in cell migration, axonal growth, and synaptic remodeling. A positive association has been reported between a missense polymorphism in CHL1 gene and schizophrenia in the Japanese population [Sakurai, K., Migita, O., Toru, M., Arinami, T., 2002. An association between a missense polymorphism in the close homologue of L1 (CHL1, CALL) gene and schizophrenia. Mol. Psychiatry 7, 412-415]. An association between a missense polymorphism in the close homologue of L1 (CHL1, CALL) gene and schizophrenia. In order to test this finding, we genotyped four SNPs in the gene in the Han Chinese population using a sample of 560 cases and 576 controls. Analysis of allele frequencies in both samples also showed strong association between SNP rs2272522 (the same marker studied by K. Sakurai) and the disease (X²=31.591, P<0.000001, OR=1.745, 95% CI=1.435–2.121). Our results confirm the positive association between CHL1 gene and schizophrenia and indicate that CHL1 may be involved in the etiology of schizophrenia.

Introduction

Cell adhesion molecules (CAM) of the immunoglobulin superfamily are involved in several processes of nervous system development, such as cell migration, axon outgrowth and fasciculation, myelination and synapse formation. Increase of neural CAM (NCAM) was found in hippocampus and prefrontal cortices of patients with schizophrenia (Vawter et al., 1999, Vawter et al., 2001). Increased neural CAM (NCAM) and decreased L1 cell adhesion molecule (L1CAM) immunoreactive proteins have been observed in the cerebrospinal fluid (CSF) of schizophrenic patients as compared to normal controls (Poltorak et al., 1995). These data showed the possibility of association between CAM and schizophrenia. Although no evidence has been found for involvement of NCAM in the neuropathology of schizophrenia, an association has been reported between polymorphisms of the L1CAM gene and schizophrenia in a Japanese Sample (Kurumaji et al., 2001).

The L1 family of cell adhesion molecules is a subfamily of the immunoglobulin superfamily of cell adhesion molecules, including four members: L1/NgCAM, close homolog of L1 (CHL1), neurofascin and NrCAM, of which all play roles in multiple functions involved in the development and function of the nervous system (Schmid and Maness, 2001). L1CAM is the founder of the L1 subfamily of cell recognition molecules and is able to enhance neurite outgrowth greatly. In human, mutations in the L1 gene are associated with a neurological syndrome called CRASH, an acronym for corpus callosum hypoplasia, retardation, adducted thumbs, spasticity and hydrocephalus (Fransen et al., 1995). Mice that do not express the L1 gene have defects in the guidance of axons of the corticospinal tract and callosal, the differentiation cortical dendrite and the regulation of hippocampal development (Cohen et al., 1997, Demyanenko et al., 1999).

Close homologue of L1 (CHL1), a newly identified member of the L1 family, is able to promote neurite elongation and neurite survival in vitro (Chen et al., 1999). CHL1 is expressed by neurons and glia in the central nervous system and by Schwann cells in the peripheral nervous system in a pattern overlapping during brain development at times of neurite outgrowth, but it is distinct from the other members of the L1 family. Expression levels of CHL1 decrease with increasing age, but is still significant in adult (Hillenbrand et al., 1999). Upregulated expression of CHL1 in lesioned neurons suggest it plays an important role in active axonal regeneration (Chaisuksunt et al., 2000a, Chaisuksunt et al., 2000b, Zhang et al., 2000). CHL1-deficient mice display aberrant connectivity of hippocampal mossy fibers and olfactory sensory axons, suggesting participation of CHL1 in the establishment of neuronal networks (Montag-Sallaz et al., 2003). It has been hypothesized that haploinsufficiency in the CHL1 gene may be responsible for mental defects in patients with 3p- syndrome, a disease characterized by a variety of anomalies, resulting from deletion of a terminal segment of the short arm of one chromosome 3 (Angeloni et al., 1999).

Evidence from neuropathology and epidemiology suggests a significant proportion of schizophrenia cases has neurodevelopmental aetiology (Chua and Murray, 1996). CHL1 could be considered to be a candidate gene for schizophrenia on the basis of the link between abnormal neurodevelopment and schizophrenia. Recently, it has been reported that a missense polymorphism in CHL1 gene is associated with schizophrenia in a Japanese sample (Sakurai et al., 2002). In order to understand the association closely, we genotyped four SNP polymorphisms (rs2055314, rs331894, rs2272522 and rs2272524) in 560 Chinese patients and 576 Chinese control individuals in this work.

Section snippets

Subjects

All subjects were Han Chinese in origin. A total of 560 unrelated schizophrenic patients (53.4% male) with a mean age 37.3±13.6 were collected from Liaoning, Guangdong and Shandong provinces of China. Consensus diagnosis of each patient was made by two independent psychiatrists according to the Diagnostic and Statistical Manual of Mental Disorders—Third Edition (DSM-III) (American Psychiatric Association, 1987) criteria for schizophrenia. Five hundred and seventy-six unrelated healthy persons

Result

In our case-control analysis, 560 schizophrenics and 576 controls were genotyped and compared. Table 2 shows the allele frequencies of the four markers. Genotypic distributions of these four polymorphisms did not deviate significantly from Hardy–Weinberg equilibrium. LD between each pair of all the SNPs is presented in Table 3.

SNP rs2272522 in Table 2 shows a statistically significant difference in allele frequencies between 576 controls and 560 patients individuals (X²=31.591, P<0.000001,

Discussion

Abnormalities in expression of CAMs has been found in the brains of individuals with schizophrenia (Poltorak et al., 1995, Vawter et al., 1999, Vawter et al., 2001). To date, no evidence has indicated alterations of CHL1, which plays an important role in neurodevelopment, in schizophrenia before.

Although many linkage studies showed negative results on chromosome 3 (Schizophrenia Linkage Collaborative Group for Chromosomes 3, 6 and 8, 1996, Hovatta et al., 1998, Maziade et al., 2001), a modestly

Acknowledgements

We are deeply grateful to all schizophrenic patients and healthy people participating in the study, as well as the psychiatrists and mental health workers for their help in the recruitment of schizophrenic patients. This work was partially funded by Roche and was supported by grants from the Ministry of Education, the National 863 and 973 Programs, the National Natural Science Foundation of China, and the Shanghai Municipal Commission for Sciences and Technology.

References (28)

V. Chaisuksunt et al.
Axonal regeneration from CNS neurons in the cerebellum and brainstem of adult rats: correlation with the patterns of expression and distribution of messenger RNAs for L1, CHL1, c-jun and growth-associated protein-43
Neuroscience
(2000)
C.M. Lewis et al.
Genome scan meta-analysis of schizophrenia and bipolar disorder: Part II. Schizophrenia
Am. J. Hum. Genet.
(2003)
M. Poltorak et al.
Disturbances in cell recognition molecules (N-CAM and L1 antigen) in the CSF of patients with schizophrenia
Exp. Neurol.
(1995)
M.P. Vawter et al.
Characterization of human cleaved N-CAM and association with schizophrenia
Exp. Neurol.
(2001)
Y. Zhang et al.
Expression of CHL1 and L1 by neurons and glia following sciatic nerve and dorsal root injury
Mol. Cell. Neurosci.
(2000)
Diagnostic and Statistical Manual of Mental Disorders, DSM-III-R
(1987)
D. Angeloni et al.
CALL gene is haploinsufficient in a 3p-syndrome patient
Am. J. Med. Genet.
(1999)
V. Chaisuksunt et al.
The cell recognition molecule CHL1 is strongly upregulated by injured and regenerating thalamic neurons
J. Comp. Neurol.
(2000)
S. Chen et al.
Prevention of neuronal cell death by neural adhesion molecules L1 and CHL1
J. Neurobiol.
(1999)
S.E. Chua et al.
The neurodevelopmental theory of schizophrenia: evidence concerning structure and neuropsychology
Ann. Med.
(1996)

N.R. Cohen et al.

Errors in corticospinal axon guidance in mice lacking the neural cell adhesion molecule L1

Curr. Biol.

(1997)

G.P. Demyanenko et al.

Abnormalities in neuronal process extension, hippocampal development, and the ventricular system of L1 knockout mice

J. Neurosci.

(1999)

E. Fransen et al.

CRASH syndrome: clinical spectrum of corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraparesis and hydrocephalus due to mutations in one single gene, L1

Eur. J. Hum. Genet.

(1995)

S. Germer et al.

High-throughput SNP allele-frequency determination in pooled DNA samples by kinetic PCR

Genome Res.

(2000)

Cited by (62)

Chronic mild stress impairs latent inhibition and induces region-specific neural activation in CHL1-deficient mice, a mouse model of schizophrenia
2017, Behavioural Brain Research
Citation Excerpt :
One of the human genes found to be associated with increased risks of developing schizophrenia is the Close Homolog of L1 (CHL1) [7–9], coding for a neuronal cell adhesion molecule. Three separate studies [8,10,11] have identified an association between a functional polymorphism Leu17Phe (rs2272522) in the signal peptide region of the CHL1 gene and SZ; although no experimental data exist to date, the CHL1 Leu17Phe polymorphism could alter protein trafficking and recruitment to the membrane. Another study has identified genomic copy number variations (CNVs) of the CHL1 gene in Scottish SZ patients [9]; CNVs involve mainly loss (e.g. deletions) or gain (e.g. duplications) of up to several million base pairs of DNA sequence [12] and thus can alter gene dosage and expression (e.g., a deletion of a gene or part of a gene would leave the individual with only one functional allele, i.e., heterozygous).
Schizophrenia is a neurodevelopmental disorder characterized by abnormal processing of information and attentional deficits. Schizophrenia has a high genetic component but is precipitated by environmental factors, as proposed by the ‘two-hit’ theory of schizophrenia. Here we compared latent inhibition as a measure of learning and attention, in CHL1-deficient mice, an animal model of schizophrenia, and their wild-type littermates, under no-stress and chronic mild stress conditions. All unstressed mice as well as the stressed wild-type mice showed latent inhibition. In contrast, CHL1-deficient mice did not show latent inhibition after exposure to chronic stress. Differences in neuronal activation (c-Fos-positive cell counts) were noted in brain regions associated with latent inhibition: Neuronal activation in the prelimbic/infralimbic cortices and the nucleus accumbens shell was affected solely by stress. Neuronal activation in basolateral amygdala and ventral hippocampus was affected independently by stress and genotype. Most importantly, neural activation in nucleus accumbens core was affected by the interaction between stress and genotype. These results provide strong support for a ‘two-hit’ (genes x environment) effect on latent inhibition in CHL1-deficient mice, and identify CHL1-deficient mice as a model of schizophrenia-like learning and attention impairments.
Increased temporal discounting after chronic stress in CHL1-deficient mice is reversed by 5-HT2C agonist Ro 60-0175
2017, Neuroscience
Citation Excerpt :
Thus, plausible models for SZ phenotypes involve dysfunction of these regions, via developmental dysplasias (Fernando and Robbins, 2011); mice genetically modified to model gene abnormalities found in SZ patients provide construct validity and exhibit relevant neuroanatomical defects in one or more of these regions. One of the genes recently associated with SZ is Close Homolog to L1 (CHL1) (Sakurai et al., 2002; Chen et al., 2005; Tam et al., 2010; Shaltout et al., 2013). CHL1 is a cell adhesion molecule highly expressed during the development of the nervous system (Hillenbrand et al., 1999) and involved in hippocampal neurotransmission and plasticity (Montag-Sallaz et al., 2002; Leshchyns'ka et al., 2006).
Schizophrenia is a neurodevelopmental disorder in which impaired decision-making and goal-directed behaviors are core features. One of the genes associated with schizophrenia is the Close Homolog of L1 (CHL1); CHL1-deficient mice are considered a model of schizophrenia-like deficits, including sensorimotor gating, interval timing and spatial memory impairments. Here we investigated temporal discounting in CHL1-deficient (KO) mice and their wild-type littermates. Although no discounting differences were found under baseline conditions, CHL1-KO mice showed increased impulsive choice following chronic unpredictable stress (fewer % larger-later choices, and reduced area under the discounting curve). Stressed CHL1-KO mice also showed decreased neuronal activation (number of cFos positive neurons) in the discounting task in the prelimbic cortex and dorsal striatum, areas thought to be part of executive and temporal processing circuits. Impulsive choice alterations were reversed by the 5-HT2C agonist Ro 60-0175. Our results provide evidence for a gene x environment, double-hit model of stress-related decision-making impairments, and identify CHL1-deficient mice as a mouse model for these deficits in regard to schizophrenia-like phenotypes.
Interaction between DISC1 and CHL1 in regulation of neurite outgrowth
2016, Brain Research
Disrupted-in-schizophrenia 1 (DISC1), a gene susceptible for major mental illnesses, including schizophrenia, plays multiple roles in neural development, including neuronal proliferation, maturation, migration and neurite outgrowth. DISC1 regulates neurite length via interaction with several intracellular proteins, such as NDEL1, FEZ1 and dysbindin. However, the signal transduction mechanism upstream of DISC1 in regulating neurite outgrowth remains to be elucidated. Here we show that DISC1 interacts with the intracellular domain of close homolog of L1 (CHL1), a member of the L1 family of neural cell adhesion molecules. DISC1 and CHL1 proteins co-localize in growth cones of cortical neurons. Moreover, in neurite outgrowth assay, CHL1 rescues the inhibitory effect of DISC1 on the initial phase of neurite outgrowth. Considering the fact that CHL1 also plays crucial roles in neural development, and its coding gene is associated with schizophrenia, our findings indicate that DISC1 and CHL1 may engage in physical and functional interaction in neural development, supporting the notion that DISC1 regulates neurite outgrowth with a receptor belonging to the neural cell adhesion molecules, and disruption of such interaction may contribute to increased risk for schizophrenia.
Mutations in human DNA methyltransferase DNMT1 induce specific genome-wide epigenomic and transcriptomic changes in neurodevelopment
2023, Human Molecular Genetics
Brain-Derived Neurotrophic Factor Val66Met Genotype Modulates Latent Inhibition: Relevance for Schizophrenia
2023, Schizophrenia Bulletin
CHL1 depletion affects dopamine receptor D2-dependent modulation of mouse behavior
2023, Frontiers in Behavioral Neuroscience

View all citing articles on Scopus

View full text

Case-control association study of the close homologue of L1 (CHL1) gene and schizophrenia in the Chinese population

Abstract

Introduction

Section snippets

Subjects

Result

Discussion

Acknowledgements

Neuroscience

Am. J. Hum. Genet.

Exp. Neurol.

Exp. Neurol.

Mol. Cell. Neurosci.

Diagnostic and Statistical Manual of Mental Disorders, DSM-III-R

CALL gene is haploinsufficient in a 3p-syndrome patient

Am. J. Med. Genet.

The cell recognition molecule CHL1 is strongly upregulated by injured and regenerating thalamic neurons

J. Comp. Neurol.

Prevention of neuronal cell death by neural adhesion molecules L1 and CHL1

J. Neurobiol.

The neurodevelopmental theory of schizophrenia: evidence concerning structure and neuropsychology

Ann. Med.