Biology subjects

Marazita, M. L.

Publications and source records attributed to Marazita, M. L..

5 recordsLinked to original sources

bioRxiv2018

Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 are associated with gestational duration

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. We conducted a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 was associated with gestational duration; the association was replicated in 9,291 additional infants (combined P = 3.96 x 10-14). Analysis of 15,536 mother-child pairs showed that the association was driven by fetal rather than maternal genotype. Functional experiments showed that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.

genetics↗

bioRxiv2018

Inferring Disease Risk Genes from Sequencing Data in Multiplex Pedigrees Through Sharing of Rare Variants

We previously demonstrated how sharing of rare variants (RVs) in distant affected relatives can be used to identify variants causing a complex and heterogeneous disease. This approach tested whether single RVs were shared by all sequenced affected family members. However, as with other study designs, joint analysis of several RVs (e.g. within genes) is sometimes required to obtain sufficient statistical power. Further, phenocopies can lead to false negatives for some causal RVs if complete sharing among affecteds is required. Here we extend our methodology (Rare Variant Sharing, RVS) to address these issues. Specifically, we introduce gene-based analyses, refine RV definition based on haplotypes, and introduce a partial sharing test based on RV sharing probabilities for subsets of affected family members. RVS also has the desirable features of not requiring external estimates of variant frequency or control samples, provides functionality to assess and address violations of key assumptions, and is available as open source software for genome-wide analysis. Simulations including phenocopies, based on the families of an oral cleft study, revealed the partial and complete sharing versions of RVS achieved similar statistical power compared to alternative methods (RareIBD and the Gene-Based Segregation Test), and had superior power compared to the pedigree Variant Annotation, Analysis and Search Tool (pVAAST) linkage statistic. In studies of multiplex cleft families, analysis of rare single nucleotide variants in the exome of 151 affected relatives from 54 families revealed no significant excess sharing in any one gene, but highlighted different patterns of sharing revealed by the complete and partial sharing tests.

genetics↗

bioRxiv2018

Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology

There is increasing evidence that genetic risk variants for non-syndromic cleft lip/palate (nsCL/P) are also associated with normal-range variation in facial morphology. However, previous analyses are mostly limited to candidate SNPs and findings have not been consistently replicated. Here, we used polygenic risk scores (PRS) to test for genetic overlap between nsCL/P and seven biologically relevant facial phenotypes. Where evidence was found of genetic overlap, we used bidirectional Mendelian randomization (MR) to test the hypothesis that genetic liability to nsCL/P is causally related to implicated facial phenotypes. Across 5,804 individuals of European ancestry from two studies, we found strong evidence, using PRS, of genetic overlap between nsCL/P and philtrum width; a 1 S.D. increase in nsCL/P PRS was associated with a 0.10 mm decrease in philtrum width (95% C.I. 0.054, 0.146; P = 0.00002). Follow-up MR analyses supported a causal relationship; genetic variants for nsCL/P homogeneously cause decreased philtrum width. In addition to the primary analysis, we also identified two novel risk loci for philtrum width at 5q22.2 and 7p15.2 in our Genome-wide Association Study (GWAS) of 6,136 individuals. Our results support a liability threshold model of inheritance for nsCL/P, related to abnormalities in development of the philtrum.

genetics↗

bioRxiv2018

Detection of de novo copy number deletions from targeted sequencing of trios

De novo copy number deletions have been implicated in many diseases, but there is no formal method to date however that identifies de novo deletions in parent-offspring trios from capture-based sequencing platforms. We developed Minimum Distance for Targeted Sequencing (MDTS) to fill this void. MDTS has similar sensitivity (recall), but a much lower false positive rate compared to less specific CNV callers, resulting in a much higher positive predictive value (precision). MDTS also exhibited much better scalability, and is available as open source software at github.com/JMF47/MDTS.

bioinformatics↗

bioRxiv2017

Consortium genome-wide meta-analysis for childhood dental caries traits

Prior studies suggest dental caries traits in children and adolescents are partially heritable, but there has been no large-scale consortium genome-wide association study (GWAS) to date. We therefore performed GWAS for caries in participants aged 2.5-18.0 years from 9 contributing centers. Phenotype definitions were created for the presence or absence of treated or untreated caries, stratified by primary and permanent dentition. All studies tested for association between caries and genotype dosage (imputed to Haplotype Reference Consortium or 1000 Genomes phase 1 version 3 panels) accounting for population stratification. Fixed-effects meta-analysis was performed weighted by inverse standard error. Analysis included up to 19,003 individuals (7,530 affected) for primary teeth and 13,353 individuals (5,875 affected) for permanent teeth. Evidence for association with caries status was observed at rs1594318-C for primary teeth (intronic within ALLC, Odds Ratio (OR) 0.85, Effect Allele Frequency (EAF) 0.60, p 4.13e-8) and rs7738851-A (intronic within NEDD9, OR 1.28, EAF 0.85, p 1.63e-8) for permanent teeth. Consortium-wide estimated heritability of caries was low (h2 of 1% [95% CI: 0%:7%] and 6% [95% CI 0%:13%] for primary and permanent dentitions, respectively) compared to corresponding within-study estimates (h2 of 28%, [95% CI: 9%:48%] and 17% [95% CI:2%:31%]) or previously published estimates. This study was designed to identify common genetic variants with modest effects which are consistent across different populations. We found few single variants associated with caries status under these assumptions. Phenotypic heterogeneity between cohorts and limited statistical power will have contributed; these findings could also reflect complexity not captured by our study design, such as genetic effects which are conditional on environmental exposure.\n\nAuthor summaryDental caries (tooth decay) is a common disease in children. Previous studies suggest genetic factors alter caries risk, but to date there is a gap of knowledge in identifying which specific genetic variants are responsible. We undertook analysis in a consortium including around 19,000 children and investigated whether any of 8 million common genetic variants were associated with risk of caries in primary (milk) or permanent teeth. If identified, these variants are used as tags to highlight genes which may be involved in a disease. We identified variants in two loci associated with caries status; in the primary (rs1594318) and permanent dentition (rs7738851). The former is intronic in ALLC, a gene with poorly understood function. The latter is an intronic variant within NEDD9, a gene which has several known functions including a role in development of craniofacial structures. To gain a more comprehensive understanding of genetic effects which influence caries larger studies and a better understanding of environmental modifiers or interactions with genetic effects are required.

genetics↗