A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis

Bell et al. report 46 new loci associated with biomarkers of iron homeostasis, including ferritin levels, iron binding capacity, and iron saturation, in the Icelandic, Danish and UK populations. The associated loci point to new iron-regulating proteins and important genetic differences between men and women

Peri-operative red blood cell transfusion in neonates and infants: NEonate and Children audiT of Anaesthesia pRactice IN Europe: A prospective European multicentre observational study

BACKGROUND: Little is known about current clinical practice concerning peri-operative red blood cell transfusion in neonates and small infants. Guidelines suggest transfusions based on haemoglobin thresholds ranging from 8.5 to 12 g dl-1, distinguishing between children from birth to day 7 (week 1), from day 8 to day 14 (week 2) or from day 15 (≥week 3) onwards. OBJECTIVE: To observe peri-operative red blood cell transfusion practice according to guidelines in relation to patient outcome. DESIGN: A multicentre observational study. SETTING: The NEonate-Children sTudy of Anaesthesia pRactice IN Europe (NECTARINE) trial recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. PATIENTS: The data included 5609 patients undergoing 6542 procedures. Inclusion criteria was a peri-operative red blood cell transfusion. MAIN OUTCOME MEASURES: The primary endpoint was the haemoglobin level triggering a transfusion for neonates in week 1, week 2 and week 3. Secondary endpoints were transfusion volumes, 'delta haemoglobin' (preprocedure - transfusion-triggering) and 30-day and 90-day morbidity and mortality. RESULTS: Peri-operative red blood cell transfusions were recorded during 447 procedures (6.9%). The median haemoglobin levels triggering a transfusion were 9.6 [IQR 8.7 to 10.9] g dl-1 for neonates in week 1, 9.6 [7.7 to 10.4] g dl-1 in week 2 and 8.0 [7.3 to 9.0] g dl-1 in week 3. The median transfusion volume was 17.1 [11.1 to 26.4] ml kg-1 with a median delta haemoglobin of 1.8 [0.0 to 3.6] g dl-1. Thirty-day morbidity was 47.8% with an overall mortality of 11.3%. CONCLUSIONS: Results indicate lower transfusion-triggering haemoglobin thresholds in clinical practice than suggested by current guidelines. The high morbidity and mortality of this NECTARINE sub-cohort calls for investigative action and evidence-based guidelines addressing peri-operative red blood cell transfusions strategies. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02350348

A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis

Abstract: Iron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N = 246,139), total iron binding capacity (N = 135,430), iron (N = 163,511) and transferrin saturation (N = 131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation

Ethnic inequalities in the incidence of diagnosis of severe mental illness in England: a systematic review and new meta-analyses for non-affective and affective psychoses.

This is a post-peer-review, pre-copyedit version of an article published in Social Psychiatry and Psychiatric Epidemiology. The final authenticated version is available online at: https://doi.org/10.1007/s00127-019-01758-yPURPOSE: Although excess risks particularly for a diagnosis of schizophrenia have been identified for ethnic minority people in England and other contexts, we sought to identify and synthesise up-to-date evidence (2018) for affective in addition to non-affective psychoses by specific ethnic groups in England. METHODS: Systematic review and meta-analysis of ethnic differences in diagnosed incidence of psychoses in England, searching nine databases for reviews (citing relevant studies up to 2009) and an updated search in three databases for studies between 2010 and 2018. Studies from both searches were combined in meta-analyses allowing coverage of more specific ethnic groups than previously. RESULTS: We included 28 primary studies. Relative to the majority population, significantly higher risks of diagnosed schizophrenia were found in Black African (Relative risk, RR 5.72, 95% CI 3.87-8.46, n = 9); Black Caribbean (RR 5.20, 95% CI 4.33-6.24, n = 21); South Asian (RR 2.27, 95% CI 1.63-3.16, n = 14); White Other (RR 2.24, 95% CI 1.59-3.14, n = 9); and Mixed Ethnicity people (RR 2.24, 95% CI 1.32-3.80, n = 4). Significantly higher risks for diagnosed affective psychoses were also revealed: Black African (RR 4.07, 95% CI 2.27-7.28, n = 5); Black Caribbean (RR 2.91, 95% CI 1.78-4.74, n = 16); South Asian (RR 1.71, 95% CI 1.07-2.72, n = 8); White Other (RR 1.55, 95% CI 1.32-1.83, n = 5); Mixed Ethnicity (RR 6.16, 95% CI 3.99-9.52, n = 4). CONCLUSIONS: The risk for a diagnosis of non-affective and affective psychoses is particularly elevated for Black ethnic groups, but is higher for all ethnic minority groups including those previously not assessed through meta-analyses (White Other, Mixed Ethnicity). This calls for further research on broader disadvantages affecting ethnic minority people.Lankelly Chase Foundatio

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