Elena Bacchelli
Università di Bologna, Pharmacy and Biotechnology, Faculty Member
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Research Interests: Genetics, Complementary and Alternative Medicine, Methods, Humans, Child, and 15 moreHaplotypes, Female, Child and Adolescent Psychiatry, Male, Cluster Analysis, Gene, Autism Spectrum Disorder, Middle Aged, Genotype, Adult, Linkage Disequilibrium, Haplotype, Cohort Studies, Child development disorders, and Genetic predisposition to disease
ObjectiveThe objective of this study was to aggregate data for the first genomewide association study meta‐analysis of cluster headache, to identify genetic risk variants, and gain biological insights.MethodsA total of 4,777 cases (3,348... more
ObjectiveThe objective of this study was to aggregate data for the first genomewide association study meta‐analysis of cluster headache, to identify genetic risk variants, and gain biological insights.MethodsA total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse‐variance genomewide association meta‐analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans‐ancestry meta‐analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome‐wide association, fine‐mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyse...
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genome-wide scan for common alleles affecting risk for autism.
Research Interests: Genetics, Developmental Biology, Autism, Biology, Developmental neuroscience, and 15 moreGene expression, Human, Female, Heritability, Autism Spectrum Disorder, Clinical Sciences, Genotyping, DDC, Gene Set Analysis, Chromosomes, Case Control Studies, Genetic Correlation, Adaptor Proteins, Brain Disorders, and Genetic predisposition to disease
115. Holt R, Barnby G, Maestrini E, Bacchelli E, Brocklebank D, Sousa I, Mulder E, Kantojarvi K, Järvelä I, Klauck S, Poustka F, Bailey AJ, Monaco AP and the EU Autism MOLGEN Consortium. Linkage and Candidate Gene Studies of Autism Spectrum Disorders in European Populations. Eur J Hum Genet 18: 1...more
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We examined the potential benefits of neuroimaging measurements across the first 5 years of life in detecting early comorbid or etiological signs of autism spectrum disorder (ASD). In particular, we analyzed the prevalence of... more
We examined the potential benefits of neuroimaging measurements across the first 5 years of life in detecting early comorbid or etiological signs of autism spectrum disorder (ASD). In particular, we analyzed the prevalence of neuroradiologic findings in routine magnetic resonance imaging (MRI) scans of a group of 117 ASD children younger than 5 years old. These data were compared to those reported in typically developing (TD) children. MRI findings in children with ASD were analyzed in relation to their cognitive level, severity of autistic symptoms, and the presence of electroencephalogram (EEG) abnormalities. The MRI was rated abnormal in 55% of children with ASD with a significant prevalence in the high-functioning subgroup compared to TD children. We report significant incidental findings of mega cisterna magna, ventricular anomalies and abnormal white matter signal intensity in ASD without significant associations between these MRI findings and EEG features. Based on these resu...
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The identification of genetic variants underlying autism spectrum disorders (ASDs) may contribute to a better understanding of their underlying biology. To examine the possible role of a specific type of compound heterozygosity in ASD,... more
The identification of genetic variants underlying autism spectrum disorders (ASDs) may contribute to a better understanding of their underlying biology. To examine the possible role of a specific type of compound heterozygosity in ASD, namely, the occurrence of a deletion together with a functional nucleotide variant on the remaining allele, we sequenced 550 genes in 149 individuals with ASD and their deletion-transmitting parents. This approach allowed us to identify additional sequence variants occurring in the remaining allele of the deletion. Our main goal was to compare the rate of sequence variants in remaining alleles of deleted regions between probands and the deletion-transmitting parents. We also examined the predicted functional effect of the identified variants using Combined Annotation-Dependent Depletion (CADD) scores. The single nucleotide variant-deletion co-occurrence was observed in 13.4% of probands, compared with 8.1% of parents. The cumulative burden of sequence...
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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 copy-number variants (CNVs) and protein-disrupting... more
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 copy-number 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 c...
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Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders with high heritability, although their underlying genetic factors are still largely unknown. Here we present a comprehensive genetic characterization of two ASD... more
Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders with high heritability, although their underlying genetic factors are still largely unknown. Here we present a comprehensive genetic characterization of two ASD siblings from Sardinia by genome-wide copy number variation analysis and whole exome sequencing (WES), to identify novel genetic alterations associated with this disorder. Single nucleotide polymorphism (SNP) array data revealed a rare microdeletion involving CAPG, ELMOD3, and SH2D6 genes, in both siblings. CAPG encodes for a postsynaptic density (PSD) protein known to regulate spine morphogenesis and synaptic formation. The reduced CAPG mRNA and protein expression levels in ASD patients, in the presence of hemizygosity or a particular genetic and/or epigenetic background, highlighted the functional relevance of CAPG as a candidate gene for ASD. WES analysis led to the identification in both affected siblings of a rare frameshift mutation in VDAC3, ...
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Pilocytic astrocytoma (PA) is the most common glioma in pediatric patients and occurs in different locations. Chromosomal alterations are mostly located at chromosome 7q34 comprising theoncogene with consequent activation of the... more
Pilocytic astrocytoma (PA) is the most common glioma in pediatric patients and occurs in different locations. Chromosomal alterations are mostly located at chromosome 7q34 comprising theoncogene with consequent activation of the mitogen-activated protein kinase pathway. Although genetic and epigenetic alterations characterizing PA from different localizations have been reported, the role of epigenetic alterations in PA development is still not clear. The aim of this study was to investigate whether distinctive methylation patterns may define biologically relevant groups of PAs. Integrated DNA methylation analysis was performed on 20 PAs and 4 normal brain samples by Illumina Infinium HumanMethylation27 BeadChips. We identified distinct methylation profiles characterizing PAs from different locations (infratentorial vs supratentorial) and tumors with onset before and after 3 years of age. These results suggest that PA may be related to the specific brain site where the tumor arises f...
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Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo... more
Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.
Research Interests: Intelligence, Biology, Intellectual Disability, Medicine, Biological Sciences, and 15 moreHumans, Child, Female, Male, Genetic Association Studies, Phenotype, Ethnic Groups, Autism Spectrum Disorder, Family Health, Adult, Educational Status, Genetic variation, Risk Factors, Cohort Studies, and Medical and Health Sciences
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Common variants contribute significantly to the genetics of autism spectrum disorder (ASD), although the identification of individual risk polymorphisms remains still elusive due to their small effect sizes and limited sample sizes... more
Common variants contribute significantly to the genetics of autism spectrum disorder (ASD), although the identification of individual risk polymorphisms remains still elusive due to their small effect sizes and limited sample sizes available for association studies. During the last decade several genome-wide association studies (GWAS) have enabled the detection of a few plausible risk variants. The three main studies are family-based and pointed at SEMA5A (rs10513025), MACROD2 (rs4141463) and MSNP1 (rs4307059). In our study we attempted to replicate these GWAS hits using a case-control association study in five European populations of ASD patients and gender-matched controls, all Caucasians. Results showed no association of individual variants with ASD in any of the population groups considered or in the combined European sample. We performed a meta-analysis study across five European populations for rs10513025 (1,904 ASD cases and 2,674 controls), seven European populations for rs4...
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Disorders of the brain exhibit considerable epidemiological comorbidity and frequently share symptoms, provoking debate about the extent of their etiologic overlap. We quantified the genetic sharing of 25 brain disorders based on summary... more
Disorders of the brain exhibit considerable epidemiological comorbidity and frequently share symptoms, provoking debate about the extent of their etiologic overlap. We quantified the genetic sharing of 25 brain disorders based on summary statistics from genome-wide association studies of 215,683 patients and 657,164 controls, and their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders show substantial sharing of common variant risk, while neurological disorders appear more distinct from one another. We observe limited evidence of sharing between neurological and psychiatric disorders, but do identify robust sharing between disorders and several cognitive measures, as well as disorders and personality types. We also performed extensive simulations to explore how power, diagnostic misclassification and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a source of risk for brain diso...
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Research Interests: Genetics, Biology, Low Frequency, Molecular Psychiatry, Biological Sciences, and 15 moreMolecular, Humans, Genetic Testing, Mice, cyclic AMP, Female, Animals, Male, Pedigree, Genotype, Linkage Disequilibrium, Genetic variation, Association Analysis, Autistic disorder, and Medical and Health Sciences
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Research Interests: Genetics, Human Genetics, Polymorphism, Complementary and Alternative Medicine, Biology, and 15 moreMolecular Genetics, Medicine, Humans, Female, Male, Infant, Pedigree, High Pressure Liquid Chromatography, Protein Binding, DNA binding proteins, DNA mutational analysis, Autistic disorder, Mutation analysis, Direct sequence, and Paediatrics and reproductive medicine
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Despite the strong genetic basis of autism spectrum disorders (ASD), research efforts in the last decade have not been successful in the identification of confirmed susceptibility genes. We review the present status of genetic linkage,... more
Despite the strong genetic basis of autism spectrum disorders (ASD), research efforts in the last decade have not been successful in the identification of confirmed susceptibility genes. We review the present status of genetic linkage, candidate gene, and association studies, pointing out the limitations of these approaches and the challenge of dealing with the clinical and genetic complexity of autism. Finally, we outline how recent technological and bioinformatic advances, together with an increasing understanding of the structure of the human genome, have set the stage to perform more comprehensive and well powered studies, possibly leading to a turning point in the understanding of the genetic basis of this devastating disorder.
Research Interests: Genetics, Autism, Biology, Molecular Genetics, Medicine, and 14 moreHumans, Child, Linkage, Genetic determinism, Genetic linkage analysis, Genes, Autism Spectrum Disorder, Clinical Sciences, Spectrum, Single Nucleotide Polymorphism, Linkage Disequilibrium, Candidate Genes, Genetic Mapping, and Chromosome aberrations
Autism Spectrum Disorder (ASD) is a highly heterogeneous neuropsychiatric disorder with a strong genetic component. The genetic architecture is complex, consisting of a combination of common low-risk and more penetrant rare variants.... more
Autism Spectrum Disorder (ASD) is a highly heterogeneous neuropsychiatric disorder with a strong genetic component. The genetic architecture is complex, consisting of a combination of common low-risk and more penetrant rare variants. Voltage-gated calcium channels (VGCCs or Cav) genes have been implicated as high-confidence susceptibility genes for ASD, in accordance with the relevant role of calcium signaling in neuronal function. In order to further investigate the involvement of VGCCs rare variants in ASD susceptibility, we performed whole genome sequencing analysis in a cohort of 105 families, composed of 124 ASD individuals, 210 parents and 58 unaffected siblings. We identified 53 rare inherited damaging variants in Cav genes, including genes coding for the principal subunit and genes coding for the auxiliary subunits, in 40 ASD families. Interestingly, biallelic rare damaging missense variants were detected in the CACNA1H gene, coding for the T-type Cav3.2 channel, in ASD prob...
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Autism is a severe neurodevelopmental disorder with a complex genetic predisposition. Linkage findings from several genome scans suggest the presence of an autism susceptibility locus on chromosome 2q24-q33, making this region the focus... more
Autism is a severe neurodevelopmental disorder with a complex genetic predisposition. Linkage findings from several genome scans suggest the presence of an autism susceptibility locus on chromosome 2q24-q33, making this region the focus of candidate gene and association studies. Recently, significant association with autism has been reported for single-nucleotide polymorphisms (SNPs) in the SLC25A12 and CMYA3 genes on chromosome 2q. We attempted to replicate these findings in the collection of families from the International Molecular Genetic Study of Autism Consortium (IMGSAC), using the transmission disequilibrium test and case-control comparison. Our study failed to reveal any significant association for the SNPs tested at either locus, suggesting that these variants are unlikely to play a major role in genetic susceptibility to autism in our sample.