X-Linked Genes and Risk of Orofacial Clefts: Evidence from Two Population-Based Studies in Scandinavia

Background: Orofacial clefts are common birth defects of complex etiology, with an excess of males among babies with cleft lip and palate, and an excess of females among those with cleft palate only. Although genes on the X chromosome have been implicated in clefting, there has been no association analysis of X-linked markers. Methodology/Principal Findings: We added new functionalities in the HAPLIN statistical software to enable association analysis of X-linked markers and an exploration of various causal scenarios relevant to orofacial clefts. Genotypes for 48 SNPs in 18 candidate genes on the X chromosome were analyzed in two population-based samples from Scandinavia (562 Norwegian and 235 Danish case-parent triads). For haplotype analysis, we used a sliding-window approach and assessed isolated cleft lip with or without cleft palate (iCL/P) separately from isolated cleft palate only (iCPO). We tested three statistical models in HAPLIN, allowing for: i) the same relative risk in males and females, ii) sex-specific relative risks, and iii) X-inactivation in females. We found weak but consistent associations with the oral-facial-digital syndrome 1 (OFD1) gene (formerly known as CXORF5) in the Danish iCL/P samples across all models, but not in the Norwegian iCL/P samples. In sex-specific analyses, the association with OFD1 was in male cases only. No analyses showed associations with iCPO in either the Norwegian or the Danish sample. Conclusions: The association of OFD1 with iCL/P is plausible given the biological relevance of this gene. However, the lack of replication in the Norwegian samples highlights the need to verify these preliminary findings in other large datasets. More generally, the novel analytic methods presented here are widely applicable to investigations of the role of X-linked genes in complex traits

Variants in the fetal genome near FLT1 are associated with risk of preeclampsia.

: Preeclampsia, which affects approximately 5% of pregnancies, is a leading cause of maternal and perinatal death. The causes of preeclampsia remain unclear, but there is evidence for inherited susceptibility. Genome-wide association studies (GWAS) have not identified maternal sequence variants of genome-wide significance that replicate in independent data sets. We report the first GWAS of offspring from preeclamptic pregnancies and discovery of the first genome-wide significant susceptibility locus (rs4769613; P = 5.4 × 10(-11)) in 4,380 cases and 310,238 controls. This locus is near the FLT1 gene encoding Fms-like tyrosine kinase 1, providing biological support, as a placental isoform of this protein (sFlt-1) is implicated in the pathology of preeclampsia. The association was strongest in offspring from pregnancies in which preeclampsia developed during late gestation and offspring birth weights exceeded the tenth centile. An additional nearby variant, rs12050029, associated with preeclampsia independently of rs4769613. The newly discovered locus may enhance understanding of the pathophysiology of preeclampsia and its subtypes.<br/

Schmidt-hammer exposure ages from periglacial patterned ground (sorted circles) in Jotunheimen, Norway, and their interpretative problems

© 2016 Swedish Society for Anthropology and Geography Periglacial patterned ground (sorted circles and polygons) along an altitudinal profile at Juvflya in central Jotunheimen, southern Norway, is investigated using Schmidt-hammer exposure-age dating (SHD). The patterned ground surfaces exhibit R-value distributions with platycurtic modes, broad plateaus, narrow tails, and a negative skew. Sample sites located between 1500 and 1925 m a.s.l. indicate a distinct altitudinal gradient of increasing mean R-values towards higher altitudes interpreted as a chronological function. An established regional SHD calibration curve for Jotunheimen yielded mean boulder exposure ages in the range 6910 ± 510 to 8240 ± 495 years ago. These SHD ages are indicative of the timing of patterned ground formation, representing minimum ages for active boulder upfreezing and maximum ages for the stabilization of boulders in the encircling gutters. Despite uncertainties associated with the calibration curve and the age distribution of the boulders, the early-Holocene age of the patterned ground surfaces, the apparent cessation of major activity during the Holocene Thermal Maximum (HTM) and continuing lack of late-Holocene activity clarify existing understanding of the process dynamics and palaeoclimatic significance of large-scale sorted patterned ground as an indicator of a permafrost environment. The interpretation of SHD ages from patterned ground surfaces remains challenging, however, owing to their diachronous nature, the potential for a complex history of formation, and the influence of local, non-climatic factors

The catatonic dilemma expanded

Catatonia is a common syndrome that was first described in the literature by Karl Kahlbaum in 1874. The literature is still developing and remains unclear on many issues, especially classification, diagnosis, and pathophysiology. Clinicians caring for psychiatric patients with catatonic syndromes continue to face many dilemmas in diagnosis and treatment. We discuss many of the common problems encountered in the care of a catatonic patient, and discuss each problem with a review of the literature. Focus is on practical aspects of classification, epidemiology, differential diagnosis, treatment, medical comorbidity, cognition, emotion, prognosis, and areas for future research in catatonic syndromes