Genome wide analysis of rare copy number variations in alcohol abuse or dependence

Rodriguez‐Lopez, Julio A.; Flórez, Gerardo; Blanco, Vanessa; Pereiro, César; Fernández, José Manuel; Fariñas, Emilio; Estévez, Valentín; Gómez-Trigo, Jesús; Gurriarán, Xaquín; Calvo, R. Castro; Sáiz, Pilar A.; Osorio, Jesús; Carrera, Indalecio; Páramo, María José; López, Nicolás; García, Ana Rosa Sepúlveda; González, Ana María; Rodriguez, Juana María; Matalobos, Manuela; Pomares, Joaquín; Longo, María Jesús; Álvarez, Susana Álvarez; Pino, Carlos; Martín, Carlos; Lorenzo, Angeles Sanchez San; Páramo, Mario; Paz, Eduardo; Díaz-Llenderozas, Francisco; Pérez, Manuela; Gómez-Ramiro, Marta; Portes, José; Serrano, Manuel; Miguel, Domingo; López-Crecente, Ana María; Bobes, Julio; García‐Portilla, Paz; Fuente, Lorena de la; Villa, Rocío; Rodríguez-Revuelta, Julia; Riera, Leonor; Rubio, Carmen; Herrero, Rocío; Vázquez, Fernando; Arrojo, Manuel; Costas, Javier

doi:10.1016/j.jpsychires.2018.06.001

Cited by 8 publications

(7 citation statements)

References 49 publications

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“…To our knowledge, only a few studies reported the use of PsychArray data for genome-wide CNV detection [10][11][12] . Hence, we established a CNV calling protocol based on three different CNV detection algorithms and set criteria to define stringent CNV calls (Supplementary Methods).…”

Section: Resultsmentioning

confidence: 99%

An integrated analysis of rare CNV and exome variation in Autism Spectrum Disorder using the Infinium PsychArray

Bacchelli

Cameli

Viggiano

et al. 2020

Sci Rep

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Autism spectrum disorder (ASD) is a neurodevelopmental condition with a complex and heterogeneous genetic etiology. While a proportion of ASD risk is attributable to common variants, rare copynumber variants (cnVs) and protein-disrupting single-nucleotide variants (SnVs) have been shown to significantly contribute to ASD etiology. We analyzed a homogeneous cohort of 127 ASD Italian families genotyped with the illumina psychArray, to perform an integrated analysis of cnVs and SnVs and to assess their contribution to ASD risk. We observed a higher burden of rare cnVs, especially deletions, in ASD individuals versus unaffected controls. Furthermore, we identified a significant enrichment of rare cnVs intersecting ASD candidate genes reported in the SfARi database. family-based analysis of rare SnVs genotyped by the psychArray also indicated an increased transmission of rare SnV variants from heterozygous parents to probands, supporting a multigenic model of ASD risk with significant contributions of both variant types. Moreover, our study reinforced the evidence for a significant role of VPS13B, WWOX, CNTNAP2, RBFOX1, MACROD2, APBA2, PARK2, GPHN, and RNF113A genes in ASD susceptibility. finally, we showed that the psychArray, besides providing useful genotyping data in psychiatric disorders, is a valuable and cost-efficient tool for genic CNV detection, down to 10 kb. Autism spectrum disorders (ASDs) are a heterogeneous group of neuropsychiatric conditions characterized by impairments in social communication, as well as the presence of restricted interests, stereotyped and repetitive behaviors. ASDs have a worldwide prevalence of about 1%, with males about four times more likely to be affected than females 1. ASDs are highly heterogeneous, both in clinical presentation and with reference to the complex risk architecture. ASD individuals often display other psychiatric and medical conditions including intellectual disability (ID), epilepsy, sleep disorders, motor deficits (hypotonia, apraxia or motor delay), attention-deficit hyperactivity disorder (ADHD), and gastrointestinal disturbances. Undoubtedly, genetic factors play a substantial role in ASD risk. With the availability of microarray and massively parallel sequencing platforms, significant progresses have been made in the last decade in elucidating the underlying genetic risk factors. There is a rising awareness that both common and rare variants contribute to ASD risk. Despite the accumulating evidence supporting a major role of common genetic variation in ASDs 2 , the relative risk conferred by each common variant is very low, thus the identification of common risk variants robustly associated to ASD requires very large sample sizes, which are just starting to be attainable thanks to massive international efforts. A recent genome-wide association meta-analysis of 18,381 ASD cases and 27,969 controls first reported common risk variants reaching genome-wide significance 3. Given the difficulties in the identification of common risk alleles, most of our current...

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Section: Resultsmentioning

confidence: 99%

An integrated analysis of rare CNV and exome variation in Autism Spectrum Disorder using the Infinium PsychArray

Bacchelli

Cameli

Viggiano

et al. 2020

Sci Rep

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“…Blood donors were not financially remunerated, making it unlikely that socially disadvantaged groups, which might have higher rates of schizophrenia, were overrepresented. Additional Galician controls, screened to discard any psychiatric diagnosis, were originally collected in Santiago de Compostela for a study of alcohol dependence 18 . Controls were also of Iberian origin, from the autonomous region of Galicia, Spain.…”

Section: Methodsmentioning

confidence: 99%

“…Additional Galician controls, screened to discard any psychiatric diagnosis, were originally collected in Santiago de Compostela for a study of alcohol dependence. 18 Controls were also of Iberian origin, from the autonomous region of Galicia, Spain.…”

Section: Subjectsmentioning

confidence: 99%

“…The collections used in this study were previously described. 18,19 2.2 | Genotyping, imputation, and quality control Samples were genotyped using the Illumina Infinium PsychArray BeadChip (Illumina, San Diego, California, USA) and standard genotyping quality control procedures were applied to the data using PLINK 1.9. 20 SNPs were eliminated based on these filters: genotyping missingness >5%, significant difference in missingness in case control status (p < 0.001), departure for Hardy-Weinberg equilibrium (p < 0.001) or minor allele frequency <0.01.…”

Section: Subjectsmentioning

confidence: 99%

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Association between psychiatric hospitalizations of patients with schizophrenia and polygenic risk scores based on genes with altered expression by antipsychotics

Facal

Arrojo

Paz

et al. 2022

Acta Psychiatr Scand

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Objective: To test whether a schizophrenia polygenic risk score (PRS) based on the subset of polymorphisms that affect brain expression of genes with altered expression by antipsychotics (exprAP PRS) is associated with psychiatric readmission of patients with schizophrenia. Methods: The study involved 427 patients with schizophrenia. Genes with altered expression by antipsychotics were extracted from the Comparative Toxigenomics Database. ExprAP PRS was estimated using the clumping and thresholding (p < 0.05) method. Two additional PRS were tested based on subsets of exprAP polymorphisms whose schizophrenia risk allele has the same (unrestored PRS) or opposite (restored PRS) direction of effect on gene expression than antipsychotics. A general SCZ PRS was tested for comparison. Logistic and ordinal regression were used to test for association of each PRS with ever readmission and admission history, an outcome based on length and number of admissions, respectively. Webgestalt was used for Gene Ontology enrichment analysis.Results: ExprAP PRS was associated with ever readmission (OR = 1.48, 95%

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“…Since these CNVs affect large gene fragments, or the whole gene, their functional consequences are huge. Currently, several studies have analyzed the association between CNVs and alcohol dependence [ 33 , 34 , 35 ]. Nevertheless, to our best knowledge, no studies analyzing CNVs in genes involved in alcohol biodisposition in alcoholic cirrhosis have been carried out.…”

Section: Introductionmentioning

confidence: 99%

Genetic Variants of Alcohol Metabolizing Enzymes and Alcohol-Related Liver Cirrhosis Risk

Ayuso

García‐Martín

Cornejo-García

et al. 2021

JPM

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Alcohol-related liver disease (ARLD) is a major public health issue caused by excessive alcohol consumption. ARLD encompasses a wide range of chronic liver lesions, alcohol-related liver cirrhosis being the most severe and harmful state. Variations in the genes encoding the enzymes, which play an active role in ethanol metabolism, might influence alcohol exposure and hence be considered as risk factors of developing cirrhosis. We conducted a case-control study in which 164 alcohol-related liver cirrhosis patients and 272 healthy controls were genotyped for the following functional single nucleotide variations (SNVs): ADH1B gene, rs1229984, rs1041969, rs6413413, and rs2066702; ADH1C gene, rs35385902, rs283413, rs34195308, rs1693482, and rs35719513; CYP2E1 gene, rs3813867. Furthermore, copy number variations (CNVs) for ADH1A, ADH1B, ADH1C, and CYP2E1 genes were analyzed. A significant protective association with the risk of developing alcohol-related liver cirrhosis was observed between the mutant alleles of SNVs ADH1B rs1229984 (Pcvalue = 0.037) and ADH1C rs283413 (Pc value = 0.037). We identified CNVs in all genes studied, ADH1A gene deletions being more common in alcohol-related liver cirrhosis patients than in control subjects, although the association lost statistical significance after multivariate analyses. Our findings support that susceptibility to alcohol-related liver cirrhosis is related to variations in alcohol metabolism genes.

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Genome wide analysis of rare copy number variations in alcohol abuse or dependence

Cited by 8 publications

References 49 publications

An integrated analysis of rare CNV and exome variation in Autism Spectrum Disorder using the Infinium PsychArray

An integrated analysis of rare CNV and exome variation in Autism Spectrum Disorder using the Infinium PsychArray

Association between psychiatric hospitalizations of patients with schizophrenia and polygenic risk scores based on genes with altered expression by antipsychotics

Genetic Variants of Alcohol Metabolizing Enzymes and Alcohol-Related Liver Cirrhosis Risk

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