27 research outputs found
Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene
Nonsyndromic orofacial clefts are common birth defects with multifactorial etiology. The
most common type is cleft lip, which occurs with or without cleft palate (nsCLP and nsCLO,
respectively). Although genetic components play an important role in nsCLP, the genetic
factors that predispose to palate involvement are largely unknown. In this study, we carried
out a meta-analysis on genetic and clinical data from three large cohorts and identified
strong association between a region on chromosome 15q13 and nsCLP (P = 8.13×10−14 for
rs1258763; relative risk (RR): 1.46, 95% confidence interval (CI): 1.32–1.61)) but not
nsCLO (P = 0.27; RR: 1.09 (0.94–1.27)). The 5 kb region of strongest association maps
downstream of Gremlin-1 (GREM1), which encodes a secreted antagonist of the BMP4
pathway. We show during mouse embryogenesis, Grem1 is expressed in the developing lip
and soft palate but not in the hard palate. This is consistent with genotype-phenotype correlations
between rs1258763 and a specific nsCLP subphenotype, since a more than two-fold
increase in risk was observed in patients displaying clefts of both the lip and soft palate but
who had an intact hard palate (RR: 3.76, CI: 1.47–9.61, Pdiff<0.05). While we did not find lip
or palate defects in Grem1-deficient mice, wild type embryonic palatal shelves developed
divergent shapes when cultured in the presence of ectopic Grem1 protein (P = 0.0014). The
present study identified a non-coding region at 15q13 as the second, genome-wide significant
locus specific for nsCLP, after 13q31. Moreover, our data suggest that the closely
located GREM1 gene contributes to a rare clinical nsCLP entity. This entity specifically
involves abnormalities of the lip and soft palate, which develop at different time-points and
in separate anatomical regions.Clefts of the lip and palate are common birth defects, and require long-term multidisciplinary
management. Their etiology involves genetic factors and environmental influences
and/or a combination of both, however, these interactions are poorly defined. Moreover,
although clefts of the lip may or may not involve the palate, the determinants predisposing
to specific subphenotypes are largely unknown. Here we demonstrate that variations in
the non-coding region near the GREM1 gene show a highly significant association with a
particular phenotype in which cleft lip and cleft palate co-occ
Whole-genome sequencing reveals host factors underlying critical COVID-19
Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease
Second prospective, Pharmacoepidemiologic database analysis of Phentermine and Topiramate extended-release usage from a representative us sample of Older Patients
Remarkable role of annealing time on anatase phase titania nanotubes and its photoelectrochemical response
Large-scale genotyping identifies a new locus at 22q13.2 associated with female breast size
Journal of Medical Genetics5010666 - 673JMDG