Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura

Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.</p

Causes of Perinatal Death at a Tertiary Care Hospital in Northern Tanzania 2000-2010: A Registry Based Study.

Perinatal mortality reflects maternal health as well as antenatal, intrapartum and newborn care, and is an important health indicator. This study aimed at classifying causes of perinatal death in order to identify categories of potentially preventable deaths. We studied a total of 1958 stillbirths and early neonatal deaths above 500 g between July 2000 and October 2010 registered in the Medical Birth Registry and neonatal registry at Kilimanjaro Christian Medical Centre (KCMC) in Northern Tanzania. The deaths were classified according to the Neonatal and Intrauterine deaths Classification according to Etiology (NICE). Overall perinatal mortality was 57.7/1000 (1958 out of 33 929), of which 1219 (35.9/1000) were stillbirths and 739 (21.8/1000) were early neonatal deaths. Major causes of perinatal mortality were unexplained asphyxia (n=425, 12.5/1000), obstetric complications (n=303, 8.9/1000), maternal disease (n=287, 8.5/1000), unexplained antepartum stillbirths after 37 weeks of gestation (n= 219, 6.5/1000), and unexplained antepartum stillbirths before 37 weeks of gestation (n=184, 5.4/1000). Obstructed/prolonged labour was the leading condition (251/303, 82.8%) among the obstetric complications. Preeclampsia/eclampsia was the leading cause (253/287, 88.2%) among the maternal conditions. When we excluded women who were referred for delivery at KCMC due to medical reasons (19.1% of all births and 36.0% of all deaths), perinatal mortality was reduced to 45.6/1000. This reduction was mainly due to fewer deaths from obstetric complications (from 8.9 to 2.1/1000) and maternal conditions (from 8.5 to 5.5/1000). The distribution of causes of death in this population suggests a great potential for prevention. Early identification of mothers at risk of pregnancy complications through antenatal care screening, teaching pregnant women to recognize signs of pregnancy complications, timely access to obstetric care, monitoring of labour for fetal distress, and proper newborn resuscitation may reduce some of the categories of deaths

Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality

Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.publishedVersio

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

Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (P-Bonferroni <1.06 x 10(-7)). In additional analyses in 7,278 participants,Peer reviewe

Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura

Publisher Copyright: © 2023, The Author(s).Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.Peer reviewe

Eye discomfort, headache and back pain among Mayan Guatemalan women taking part in a randomised stove intervention trial

Background: Indoor air pollution (IAP) from combustion of biomass fuels represents a global health problem, estimated to cause 1.6 million premature deaths annually. Aims: RESPIRE (Randomised Exposure Study of Pollution Indoors and Respiratory Effects) Guatemala is the first randomised controlled trial ever performed on health effects from solid fuel use. Its goal is to assess the effect of improved stoves (planchas) on exposure and health outcomes in a rural population reliant on wood fuel. Methods: Questions about symptoms were asked at baseline and periodically after the intervention, to an initial group of 504 women (259 randomly assigned to planchas (mean (standard deviation) age 27.4 (7.2) years) and 245 using traditional open fires (28.1 (7.1) years)). Levels of carbon monoxide (CO) in exhaled breath, a biomarker of recent exposure to air pollution from biomass combustion, were measured at each visit. In addition to reducing IAP levels, the plancha may also have a positive health effect by changing the working posture to an upright position. Results: A high prevalence of eye discomfort, headache and backache was found. The odds of having sore eyes and headache were substantially reduced in the plancha group relative to the group using open fires for the follow-up period (odds ratio (OR) 0.18, 95% confidence interval (CI) 0.11 to 0.29 and (OR) 0.63, 95% CI 0.42 to 0.94, respectively). Median CO in breath among women in the intervention trial was significantly lower than controls. Conclusion: In addition to reducing discomfort for women, tangible improvements in symptoms experienced by a substantial proportion of women may help to gain acceptance and wider use of planchas

Exposure to Household Air Pollution from Wood Combustion and Association with Respiratory Symptoms and Lung Function in Nonsmoking Women: Results from the RESPIRE Trial, Guatemala

Background: With 40% of the world’s population relying on solid fuel, household air pollution (HAP) represents a major preventable risk factor for COPD (chronic obstructive pulmonary disease). Meta-analyses have confirmed this relationship; however, constituent studies are observational, with virtually none measuring exposure directly. Objectives: We estimated associations between HAP exposure and respiratory symptoms and lung function in young, nonsmoking women in rural Guatemala, using measured carbon monoxide (CO) concentrations in exhaled breath and personal air to assess exposure. Methods: The Randomized Exposure Study of Pollution Indoors and Respiratory Effects (RESPIRE) Guatemala study was a trial comparing respiratory outcomes among 504 women using improved chimney stoves versus traditional cookstoves. The present analysis included 456 women with data from postintervention surveys including interviews at 6, 12, and 18 months (respiratory symptoms) and spirometry and CO (ppm) in exhaled breath measurements. Personal CO was measured using passive diffusion tubes at variable times during the study. Associations between CO concentrations and respiratory health were estimated using random intercept regression models. Results: Respiratory symptoms (cough, phlegm, wheeze, or chest tightness) during the previous 6 months were positively associated with breath CO measured at the same time of symptom reporting and with average personal CO concentrations during the follow-up period. CO in exhaled breath at the same time as spirometry was associated with lower lung function [average reduction in FEV1 (forced expiratory volume in 1 sec) for a 10% increase in CO was 3.33 mL (95% CI: –0.86, –5.81)]. Lung function measures were not significantly associated with average postintervention personal CO concentrations. Conclusions: Our results provide further support for the effects of HAP exposures on airway inflammation. Further longitudinal research modeling continuous exposure to particulate matter against lung function will help us understand more fully the impact of HAP on COPD