Author
Chao-Lin Lu
Bio: Chao-Lin Lu is an academic researcher. The author has contributed to research in topics: Single-nucleotide polymorphism & Gene. The author has an hindex of 5, co-authored 5 publications receiving 86 citations.
Papers
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TL;DR: The results indicate that DLGAP2 is a susceptible gene of schizophrenia and a haplotype (CCACCAACT) significantly associated with schizophrenia is found.
Abstract: Aberrant synaptic dysfunction is implicated in the pathogenesis of schizophrenia. The DLGAP2 gene encoding the SAP90/PSD-95-associated protein 2 (SAPAP2) located at the post-synaptic density of neuronal cells is involved in the neuronal synaptic function. This study aimed to investigate whether the DLGAP2 gene is associated with schizophrenia. We resequenced the putative promoter region and all the exons of the DLGAP2 gene in 523 patients with schizophrenia and 596 non-psychotic controls from Taiwan and conducted a case-control association analysis. We identified 19 known SNPs in this sample. Association analysis of 9 SNPs with minor allele frequency greater than 5% showed no association with schizophrenia. However, we found a haplotype (CCACCAACT) significantly associated with schizophrenia (odds ratio:2.5, p T, c.−69+13C>T, c.−69+47C>T, c.−69+55C>T at intron 1 and c.−32A>G at untranslated exon 2 of the DLGAP2 gene. These rare variants were not detected in 559 control subjects. Further reporter gene assay of these rare variants except c.−69+13C>T showed significantly elevated promoter activity than the wild type, suggesting increased DLGAP2 gene expression may contribute to the pathogenesis of schizophrenia. Our results indicate that DLGAP2 is a susceptible gene of schizophrenia.
33 citations
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TL;DR: A tendency of gender-specific association of EGR2 and EGR4 in schizophrenia is suggested, with an elevated expression of E GR2 in lympoblastoid cell lines of female schizophrenia patients and a reduced E GR4 gene expression in male schizophrenia patients.
Abstract: Objective Early growth response genes (EGR1, 2, 3, and 4) encode a family of nuclear proteins that function as transcriptional regulators. They are involved in the regulation of synaptic plasticity, learning, and memory, and are implicated in the pathogenesis of schizophrenia. Methods We conducted a genetic association analysis of 14 SNPs selected from the EGR1, 2, 3, and 4 genes of 564 patients with schizophrenia and 564 control subjects. We also conducted Western blot analysis and promoter activity assay to characterize the EGR genes associated with schizophrenia Results We did not detect a true genetic association of these 14 SNPs with schizophrenia in this sample. However, we observed a nominal over-representation of C/C genotype of rs9990 of EGR2 in female schizophrenia as compared to female control subjects (p = 0.012, uncorrected for multiple testing). Further study showed that the average mRNA level of the EGR2 gene in the lymphoblastoid cell lines of female schizophrenia patients was significantly higher than that in female control subjects (p = 0.002). We also detected a nominal association of 4 SNPs (rs6747506, rs6718289, rs2229294, and rs3813226) of the EGR4 gene that form strong linkage disequilibrium with schizophrenia in males. Reporter gene assay showed that the haplotype T-A derived from rs6747506 and rs6718289 at the promoter region had significantly reduced promoter activity compared with the haplotype A-G. Conclusion Our data suggest a tendency of gender-specific association of EGR2 and EGR4 in schizophrenia, with an elevated expression of EGR2 in lympoblastoid cell lines of female schizophrenia patients and a reduced EGR4 gene expression in male schizophrenia patients.
19 citations
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TL;DR: Wang et al. as discussed by the authors identified six genetic variants, including five known SNPs (rs145691437, rs3786431, rs201567254, rs3745051 and rs11662259), and one rare missense mutation (c.1922A>G) in this sample.
Abstract: Schizophrenia is a severe chronic mental disorder with high genetic components in its etiology. Several studies indicated that synaptic dysfunction is involved in the pathophysiology of schizophrenia. Postsynaptic synapse-associated protein 90/postsynaptic density 95-associated proteins (SAPAPs) constitute a part of the N-methyl-d-aspartate receptor-associated postsynaptic density proteins, and are involved in synapse formation. We hypothesized that genetic variants of the SAPAPs might be associated with schizophrenia. Thus, we systemically sequenced all the exons of the discs, large (Drosophila) homolog-associated protein 1 (DLGAP1) gene that encodes SAPAP1 in a sample of 121 schizophrenic patients and 120 controls from Taiwan. We totally identified six genetic variants, including five known SNPs (rs145691437, rs3786431, rs201567254, rs3745051 and rs11662259) and one rare missense mutation (c.1922A>G) in this sample. SNP- and haplotype-based analyses showed no association of these SNPs with schizophrenia. The c.1922A>G mutation that changes the amino acid lysine to arginine at codon 641 was found in one out of 121 patients, but not in 275 control subjects, suggesting it might be a patient-specific mutation. Nevertheless, bioinformatic analysis showed this mutation does not affect the function of the DLGAP1 gene and appears to be a benign variant. Hence, its relationship with the pathogenesis remains to be investigated.
18 citations
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TL;DR: The exonic regions of the DLGAP3 gene, which encodes SAP90/PSD95-associated protein 3, are resequenced and several rare missense mutations are identified and some of them might be associated with the pathogenesis of schizophrenia.
Abstract: We resequenced the exonic regions of the DLGAP3 gene, which encodes SAP90/PSD95-associated protein 3, in 215 schizophrenic patients and 215 non-psychotic controls. Seven known single-nucleotide polymorphisms (SNPs) were identified, but not associated with schizophrenia. Nevertheless, we identified several rare missense mutations and some of them might be associated with the pathogenesis of schizophrenia.
16 citations
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TL;DR: There remains much to learn about the toxic effect that prenatal cigarette smoking exposure appears to have on neurodevelopment, and further and improved studies across all fields are encouraged in order to form a complete picture of nicotine as a teratogen.
14 citations
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TL;DR: E-cigarette products are changing quickly, and many of the findings from studies of older products may not be relevant to the assessment of newer products that could be safer and more effective as nicotine delivery devices, so patterns of use and the ultimate impact on public health may differ.
Abstract: Electronic cigarettes (e-cigarettes) are products that deliver a nicotine-containing aerosol (commonly called vapor) to users by heating a solution typically made up of propylene glycol or glycerol (glycerin), nicotine, and flavoring agents (Figure 1) invented in their current form by Chinese pharmacist Hon Lik in the early 2000s.1 The US patent application describes the e-cigarette device as “an electronic atomization cigarette that functions as substitutes [sic] for quitting smoking and cigarette substitutes ” (patent No. 8,490,628 B2). By 2013, the major multinational tobacco companies had entered the e-cigarette market. E-cigarettes are marketed via television, the Internet, and print advertisements (that often feature celebrities)2 as healthier alternatives to tobacco smoking, as useful for quitting smoking and reducing cigarette consumption, and as a way to circumvent smoke-free laws by enabling users to “smoke anywhere.”3
Figure 1.
Examples of different electronic cigarette (e-cigarette) products. Reproduced from Grana et al.1
There has been rapid market penetration of e-cigarettes despite many unanswered questions about their safety, efficacy for harm reduction and cessation, and total impact on public health. E-cigarette products are changing quickly, and many of the findings from studies of older products may not be relevant to the assessment of newer products that could be safer and more effective as nicotine delivery devices. In addition, marketing and other environmental influences may vary from country to country, so patterns of use and the ultimate impact on public health may differ. The individual risks and benefits and the total impact of these products occur in the context of the widespread and continuing availability of conventional cigarettes and other tobacco products, with high levels of dual use of e-cigarettes and conventional cigarettes at the same time among adults4–8 and youth.9–11 It is important to assess e-cigarette toxicant exposure and …
961 citations
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United States Department of Health and Human Services1, Erasmus University Rotterdam2, University of California, Berkeley3, Johns Hopkins University4, Icahn School of Medicine at Mount Sinai5, University of Southern California6, Duke University7, University of Bristol8, University Medical Center Groningen9, University of California, San Francisco10, North Carolina State University11, Karolinska Institutet12, Pompeu Fabra University13, University of Paris14, University of Memphis15, Centre Hospitalier Universitaire de Grenoble16, University of Bergen17, Isfahan University of Medical Sciences18, Brigham and Women's Hospital19, Oslo University Hospital20, Utrecht University21, French Institute of Health and Medical Research22, Norwegian Institute of Public Health23, Johns Hopkins University School of Medicine24, Harvard University25, International Agency for Research on Cancer26, Paris Descartes University27, Michigan State University28, Centre national de la recherche scientifique29, Fred Hutchinson Cancer Research Center30, University of Basel31, Swiss Tropical and Public Health Institute32, Stockholm County Council33, University of Southampton34
TL;DR: This large scale meta-analysis of methylation data identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.
Abstract: Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.
646 citations
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TL;DR: Use of e-cigarettes was associated with higher odds of ever or current cigarette smoking, higher chances of established smoking, high odds of planning to quit smoking among current smokers, and, among experimenters, lower odds of abstinence from conventional cigarettes.
Abstract: Importance Electronic cigarette (e-cigarette) use is increasing rapidly among adolescents, and e-cigarettes are currently unregulated. Objective To examine e-cigarette use and conventional cigarette smoking. Design, Setting, and Participants Cross-sectional analyses of survey data from a representative sample of US middle and high school students in 2011 (n = 17 353) and 2012 (n = 22 529) who completed the 2011 and 2012 National Youth Tobacco Survey. Exposures Ever and current e-cigarette use. Main Outcomes and Measures Experimentation with, ever, and current smoking, and smoking abstinence. Results Among cigarette experimenters (≥1 puff), ever e-cigarette use was associated with higher odds of ever smoking cigarettes (≥100 cigarettes; odds ratio [OR] = 6.31; 95% CI, 5.39-7.39) and current cigarette smoking (OR = 5.96; 95% CI, 5.67-6.27). Current e-cigarette use was positively associated with ever smoking cigarettes (OR = 7.42; 95% CI, 5.63-9.79) and current cigarette smoking (OR = 7.88; 95% CI, 6.01-10.32). In 2011, current cigarette smokers who had ever used e-cigarettes were more likely to intend to quit smoking within the next year (OR = 1.53; 95% CI, 1.03-2.28). Among experimenters with conventional cigarettes, ever use of e-cigarettes was associated with lower 30-day (OR = 0.24; 95% CI, 0.21-0.28), 6-month (OR = 0.24; 95% CI, 0.21-0.28), and 1-year (OR = 0.25; 95% CI, 0.21-0.30) abstinence from cigarettes. Current e-cigarette use was also associated with lower 30-day (OR = 0.11; 95% CI, 0.08-0.15), 6-month (OR = 0.11; 95% CI, 0.08-0.15), and 1-year (OR = 0.12; 95% CI, 0.07-0.18) abstinence. Among ever smokers of cigarettes (≥100 cigarettes), ever e-cigarette use was negatively associated with 30-day (OR = 0.61; 95% CI, 0.42-0.89), 6-month (OR = 0.53; 95% CI, 0.33-0.83), and 1-year (OR = 0.32; 95% CI, 0.18-0.56) abstinence from conventional cigarettes. Current e-cigarette use was also negatively associated with 30-day (OR = 0.35; 95% CI, 0.18-0.69), 6-month (OR = 0.30; 95% CI, 0.13-0.68), and 1-year (OR = 0.34; 95% CI, 0.13-0.87) abstinence. Conclusions and Relevance Use of e-cigarettes was associated with higher odds of ever or current cigarette smoking, higher odds of established smoking, higher odds of planning to quit smoking among current smokers, and, among experimenters, lower odds of abstinence from conventional cigarettes. Use of e-cigarettes does not discourage, and may encourage, conventional cigarette use among US adolescents.
482 citations
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TL;DR: With the central localisation in the postsynapse, the DLGAP family seems to play a vital role in synaptic scaling by regulating the turnover of both ionotropic and metabotropic glutamate receptors in response to synaptic activity.
Abstract: The neurotransmitter glutamate facilitates neuronal signalling at excitatory synapses. Glutamate is released from the presynaptic membrane into the synaptic cleft. Across the synaptic cleft glutamate binds to both ion channels and metabotropic glutamate receptors at the postsynapse, which expedite downstream signalling in the neuron. The postsynaptic density, a highly specialized matrix, which is attached to the postsynaptic membrane, controls this downstream signalling. The postsynaptic density also resets the synapse after each synaptic firing. It is composed of numerous proteins including a family of Discs large associated protein 1, 2, 3 and 4 (DLGAP1-4) that act as scaffold proteins in the postsynaptic density. They link the glutamate receptors in the postsynaptic membrane to other glutamate receptors, to signalling proteins and to components of the cytoskeleton. With the central localisation in the postsynapse, the DLGAP family seems to play a vital role in synaptic scaling by regulating the turnover of both ionotropic and metabotropic glutamate receptors in response to synaptic activity. DLGAP family has been directly linked to a variety of psychological and neurological disorders. In this review we focus on the direct and indirect role of DLGAP family on schizophrenia as well as other brain diseases.
115 citations
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TL;DR: The current understanding of those autism risk genes that affect the structural connectivity of neurons is discussed, and whether and how the neuronal structure and function are affected when these genes are mutated will provide insights toward developing effective interventions aimed at improving the lives of people with autism and their families.
Abstract: Autism spectrum disorder (ASD) comprises a range of neurological conditions that affect individuals’ ability to communicate and interact with others. People with ASD often exhibit marked qualitative difficulties in social interaction, communication, and behavior. Alterations in neurite arborization and dendritic spine morphology, including size, shape, and number, are hallmarks of almost all neurological conditions, including ASD. As experimental evidence emerges in recent years, it becomes clear that although there is broad heterogeneity of identified autism risk genes, many of them converge into similar cellular pathways, including those regulating neurite outgrowth, synapse formation and spine stability, and synaptic plasticity. These mechanisms together regulate the structural stability of neurons and are vulnerable targets in ASD. In this review, we discuss the current understanding of those autism risk genes that affect the structural connectivity of neurons. We sub-categorize them into 1) cytoskeletal regulators, e.g. motors and small RhoGTPase regulators; 2) adhesion molecules, e.g. cadherins, NCAM, and neurexin superfamily; 3) cell surface receptors, e.g. glutamatergic receptors and receptor tyrosine kinases; 4) signaling molecules, e.g. protein kinases and phosphatases; and 5) synaptic proteins, e.g. vesicle and scaffolding proteins. Although the roles of some of these genes in maintaining neuronal structural stability are well studied, how mutations contribute to the autism phenotype is still largely unknown. Investigating whether and how the neuronal structure and function are affected when these genes are mutated will provide insights toward developing effective interventions aimed at improving the lives of people with autism and their families.
79 citations