Biology subjects

De Ferrari, G. V.

Publications and source records attributed to De Ferrari, G. V..

4 recordsLinked to original sources

bioRxiv2018

Common variants in ABCG8 and TRAF3 genes confer risk for gallstone disease and gallbladder cancer in admixed Latinos with Mapuche Native American ancestry

BackgroundLatin Americans and Chilean Amerindians have the highest prevalence of cholesterol gallstone disease (GSD) and gallbladder cancer (GBC) in the world. A handful of loci have been associated with GSD in populations of predominantly European ancestry, however they only explain a small portion of the population-attributable risk of the disease.\n\nMethodsWe performed a genome-wide association study (GWAS) for GSD in 1,095 admixed Latinos with Mapuche Native American Ancestry, followed by a replication analysis of 10 candidate single nucleotide polymorphisms (SNPs) with suggestive genome-wide significance (P<1x10-5) in 1,643 individuals. Disease status was assessed by cholecystectomy or abdominal ultrasonography. Logistic regression analyses were adjusted for age, sex, BMI, Type 2 Diabetes and Amerindian ancestry. Associated variants were further examined in two large GSD European populations and in a Chilean gallbladder cancer (GBC) cohort. We determined the expression levels of a novel GSD-candidate gene in normal and GSD-tissue samples.\n\nResultsWe consistently replicated the ABCG8 gene (rs11887534; P=3.24x10-8, OR=1.74) associated with GSD in admixed Latinos and identified a novel candidate signal within the TRAF3 gene on chromosome 14 (rs12882491; P=1.11x10-7, OR=1.40). ABCG8 and TRAF3 variants also conferred risk to GBC. Gene expression analyses indicated that TRAF3 levels were significantly decreased in the gallbladder (P=0.015) and the duodenal mucosa (P=0.001) of affected GSD individuals compared to healthy controls.\n\nConclusionsWe confirmed ABCG8 and identified TRAF3 both associated with GSD and GBC in admixed Latinos. Decreased TRAF3 expression levels could enhance gallbladder inflammation as is observed in GSD and GSD-associated GBC.

genetics↗

bioRxiv2018

Whole genome sequence of Mapuche-Huilliche Native Americans

BackgroundWhole human genome sequencing initiatives provide a compendium of genetic variants that help us understand population history and the basis of genetic diseases. Current data mostly focuses on Old World populations and information on the genomic structure of Native Americans, especially those from the Southern Cone is scant.\n\nResultsHere we present a high-quality complete genome sequence of 11 Mapuche-Huilliche individuals (HUI) from Southern Chile (85% genomic and 98% exonic coverage at > 30X), with 96-97% high confidence calls. We found approximately 3.1x106 single nucleotide variants (SNVs) per individual and identified 403,383 (6.9%) of novel SNVs that are not included in current sequencing databases. Analyses of large-scale genomic events detected 680 copy number variants (CNVs) and 4,514 structural variants (SVs), including 398 and 1,910 novel events, respectively. Global ancestry composition of HUI genomes revealed that the cohort represents a marginally admixed population from the Southern Cone, whose genetic component is derived from early Native American ancestors. In addition, we found that HUI genomes display highly divergent and novel variants with potential functional impact that converge in ontological categories essential in cell metabolic processes.\n\nConclusionsMapuche-Huilliche genomes contain a unique set of small- and large-scale genomic variants in functionally linked genes, which may contribute to susceptibility for the development of common complex diseases or traits in admixed Latinos and Native American populations. Our data represents an ancestral reference panel for population-based studies in Native and admixed Latin American populations.

genomics↗

bioRxiv2017

Heterogeneous Contribution of Microdeletions in the Development of Common Generalized and Focal epilepsies

BackgroundMicrodeletions are known to confer risk to epilepsy, particularly at genomic rearrangement \"hotspot\" loci. However, deciphering their role outside hotspots and risk assessment by epilepsy sub-type has not been conducted.\n\nMethodsWe assessed the burden, frequency and genomic content of rare, large microdeletions found in a previously published cohort of 1,366 patients with Genetic Generalized Epilepsy (GGE) plus two sets of additional unpublished genome-wide microdeletions found in 281 Rolandic Epilepsy (RE) and 807 Adult Focal Epilepsy (AFE) patients, totaling 2,454 cases. These microdeletion sets were assessed in a combined analysis and in sub-type specific approaches against 6,746 ethnically matched controls.\n\nResultsWhen hotspots are considered, we detected an enrichment of microdeletions in the combined epilepsy analysis (adjusted-P= 2.00x10-7; OR = 1.89; 95%-CI: 1.51-2.35), where the implicated microdeletions overlapped with rarely deleted genes and those involved in neurodevelopmental processes. Sub-type specific analyses showed that hotspot deletions in the GGE subgroup contribute most of the signal (adjusted-P = 1.22x10-12; OR = 7.45; 95%-CI = 4.20-11.97). Outside hotspot loci, microdeletions were enriched in the GGE cohort for neurodevelopmental genes (adjusted-P = 4.78x10-3; OR = 2.30; 95%-CI = 1.42-3.70), whereas no additional signal was observed for RE and AFE. Still, gene content analysis was able to identify known (NRXN1, RBFOX1 and PCDH7) and novel (LOC102723362) candidate genes affected in more than one epilepsy sub-type but not in controls.\n\nConclusionsOur results show a heterogeneous effect of recurrent and non-recurrent microdeletions as part of the genetic architecture of GGE and a minor to negligible contribution in the etiology of RE and AFE.

genetics↗

bioRxiv2017

Duplications at 19q13.33 in patients with neurodevelopmental disorders

OBJECTIVEAfter recent publication of the first patients with disease associated missense variants in GRIN2D, we evaluate the effect of copy number variation (CNV) overlapping this gene towards the presentation of neurodevelopmental disorders.\n\nMETHODSWe explored ClinVar (N{degrees}CNV = 41,398) and DECIPHER (N{degrees}CNV = 30,222) clinical databases of genomic variations for patients with copy number changes overlapping the GRIN2D gene at the 19q13.33 locus and evaluated their respective phenotype alongside their frequency, gene content and expression with publicly available reference databases.\n\nRESULTSWe identified 13 patients with microduplications at the 19q13.33 locus. The majority of CNVs arose de novo and comparable CNVs are not present in control databases. All patients were reported to have neurodevelopmental disorders and dysmorphic features as the most common clinical phenotype (N= 10/13), followed by seizures (N= 6/13) and intellectual disability (N= 5/13). All duplications shared a consensus region of 405 kb overlapping 13 genes. After screening for duplication tolerance in control populations, positive gene brain expression and gene dosage sensitivity analysis, we highlight four genes for future evaluation: CARD8, C19orf68, KDELR1 and GRIN2D, which are promising candidates for disease causality. Further, investigation of the literature especially supports GRIN2D as the best candidate gene.\n\nCONCLUSIONSOur study presents dup19q13.33 as novel duplication syndrome locus associated with neurodevelopmental disorders. CARD8, C19orf68, KDELR1 and GRIN2D are promising candidates for functional follow up.

genetics↗