Genetics of Cluster Headache Takes a Leap COMMENT

Non peer reviewe

The relation of severe malocclusion to patients’ mental and behavioral disorders, growth, and speech problems

cjaa028Severe malocclusions appear in up to 20 per cent of the population. Many neuropsychiatric diseases are likely to have a neurodevelopmental, partially genetic background with their origins as early as fetal life. However, the possible relationship between neurodevelopmental disorders and severe malocclusions is unclear. The aim of this study was in a population-based setting (270 000 inhabitants) to investigate whether patients with severe malocclusions have more mental and behavioural disorders and growth or speech problems than controls without severe malocclusion.The study group consisted of patients from the Espoo Health Care Center, Finland, born in year 2000, who were retrospectively screened for their medical and dental records, including their possible mental and behavioural disorders (i.e. attention deficit hyperactivity disorder, Asperger’s syndrome, autism, mood disorder, or broadly defined behavioural abnormalities, learning problems, mental disorders, sleep disturbances, anxiety symptoms, depressive symptoms, and eating-related symptoms) and their need of orthodontic treatment according to the Treatment Priority Index (TPI). The study group consisted of a severe malocclusion group (n =1008; TPI 8–10) and a control group (n = 1068) with no severe malocclusion (TPI 0–7).Patients with severe mandibular retrognatia (P \lt; 0.000), lip incompetence (P = 0.006), or neurodevelopmental disorders (mental and behavioural; P = 0.002) were found to have significantly more speech problems than the controls. The patients with severe malocclusions were leaner, that is, body mass index (kg/m2) \lt;17, underweight; 17–25, normal weight; \gt;25, overweight) than controls (P = 0.003), and underweight patients had a significant association with retrognathic maxilla (P \lt; 0.000) compared to normal or overweight patients. No significant relationship between neurodevelopmental disorders and severe malocclusions, that is, retrognatia of maxilla, hypodontia, and severe dental crowding was observed.Our results indicate that patients with severe mandibular retrognatia, lip incompetence, or neurodevelopmental disorders were found to have significantly more speech problems than controls. During orthodontic treatment of patients with severe malocclusion, special attention should be paid to patients with severe mandibular retrognatia, lip incompetence, and speech problems to detect signs of possible neurodevelopmental disorders and record if potential follow-up measures are in place.Peer reviewe

Systematic review of genome-wide expression studies in multiple sclerosis

Peer reviewe

Towards an understanding of genetic predisposition to migraine

Plausible genome-wide associations for episodic neurological diseases (such as migraine, epilepsy and ataxias) have been slow to emerge. The first such association was reported in a recent genome-wide association study of migraine, with quantitative expression analysis linking the variant to a nearby regulatory gene, MTDH/AEG-1. This putative mechanism, regulating the expression of the primary glutamate transporter in the brain, EAAT2/GLT-1, has interesting implications bridging the gap between Mendelian and common forms in this key group of disorders

High divergence in primate-specific duplicated regions: Human and chimpanzee Chorionic Gonadotropin Beta genes

<p>Abstract</p> <p>Background</p> <p>Low nucleotide divergence between human and chimpanzee does not sufficiently explain the species-specific morphological, physiological and behavioral traits. As gene duplication is a major prerequisite for the emergence of new genes and novel biological processes, comparative studies of human and chimpanzee duplicated genes may assist in understanding the mechanisms behind primate evolution. We addressed the divergence between human and chimpanzee duplicated genomic regions by using Luteinizing Hormone Beta (<it>LHB</it>)/Chorionic Gonadotropin Beta (<it>CGB</it>) gene cluster as a model. The placental <it>CGB </it>genes that are essential for implantation have evolved from an ancestral pituitary <it>LHB </it>gene by duplications in the primate lineage.</p> <p>Results</p> <p>We shotgun sequenced and compared the human (45,165 bp) and chimpanzee (39,876 bp) <it>LHB/CGB </it>regions and hereby present evidence for structural variation resulting in discordant number of <it>CGB </it>genes (6 in human, 5 in chimpanzee). The scenario of species-specific parallel duplications was supported (i) as the most parsimonious solution requiring the least rearrangement events to explain the interspecies structural differences; (ii) by the phylogenetic trees constructed with fragments of intergenic regions; (iii) by the sequence similarity calculations. Across the orthologous regions of <it>LHB/CGB </it>cluster, substitutions and indels contributed approximately equally to the interspecies divergence and the distribution of nucleotide identity was correlated with the regional repeat content. Intraspecies gene conversion may have shaped the <it>LHB/CGB </it>gene cluster. The substitution divergence (1.8–2.59%) exceeded two-three fold the estimates for single-copy loci and the fraction of transversional mutations was increased compared to the unique sequences (43% versus ~30%). Despite the high sequence identity among <it>LHB/CGB </it>genes, there are signs of functional differentiation among the gene copies. Estimates for d_n/d_srate ratio suggested a purifying selection on <it>LHB </it>and <it>CGB8</it>, and a positive evolution of <it>CGB1</it>.</p> <p>Conclusion</p> <p>If generalized, our data suggests that in addition to species-specific deletions and duplications, parallel duplication events may have contributed to genetic differences separating humans from their closest relatives. Compared to unique genomic segments, duplicated regions are characterized by high divergence promoted by intraspecies gene conversion and species-specific chromosomal rearrangements, including the alterations in gene copy number.</p

A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis

Genome-wide association studies (GWAS) have identified more than 50,000 unique associations with common human traits. While this represents a substantial step forward, establishing the biology underlying these associations has proven extremely difficult. Even determining which cell types and which particular gene(s) are relevant continues to be a challenge. Here, we conduct a cell-specific pathway analysis of the latest GWAS in multiple sclerosis (MS), which had analyzed a total of 47,351 cases and 68,284 healthy controls and found more than 200 non-MHC genome-wide associations. Our analysis identifies pan immune cell as well as cell-specific susceptibility genes in T cells, B cells and monocytes. Finally, genotype-level data from 2,370 patients and 412 controls is used to compute intraindividual and cell-specific susceptibility pathways that offer a biological interpretation of the individual genetic risk to MS. This approach could be adopted in any other complex trait for which genome-wide data is available.Peer reviewe

Sleep apnoea is a risk factor for severe COVID-19

Background Obstructive sleep apnoea (OSA) is associated with higher body mass index (BMI), diabetes, older age and male gender, which are all risk factors for severe COVID-19. We aimed to study if OSA is an independent risk factor for COVID-19 infection or for severe COVID-19. Methods OSA diagnosis and COVID-19 infection were extracted from the hospital discharge, causes of death and infectious diseases registries in individuals who participated in the FinnGen study (n=260 405). Severe COVID-19 was defined as COVID-19 requiring hospitalisation. Multivariate logistic regression model was used to examine association. Comorbidities for either COVID-19 or OSA were selected as covariates. We performed a meta-analysis with previous studies. Results We identified 445 individuals with COVID-19, and 38 (8.5%) of them with OSA of whom 19 out of 91 (20.9%) were hospitalised. OSA associated with COVID-19 hospitalisation independent from age, sex, BMI and comorbidities (p-unadjusted=5.13x10(-5), OR-adjusted=2.93 (95% CI 1.02 to 8.39), p-adjusted=0.045). OSA was not associated with the risk of contracting COVID-19 (p=0.25). A meta-analysis of OSA and severe COVID-19 showed association across 15 835 COVID-19 positive controls, and n=1294 patients with OSA with severe COVID-19 (OR=2.37 (95% 1.14 to 4.95), p=0.021). Conclusion Risk for contracting COVID-19 was the same for patients with OSA and those without OSA. In contrast, among COVID-19 positive patients, OSA was associated with higher risk for hospitalisation. Our findings are in line with earlier works and suggest OSA as an independent risk factor for severe COVID-19.Peer reviewe

Serum calcium and risk of migraine : a Mendelian randomization study

Migraine affects similar to 14% of the world's population, though not all predisposing causal risk factors are known. We used electronic health records, genetic co-heritability analysis, and a two-sampleMendelian Randomization (MR) design to determine if elevated serum calcium levels were associated with risk of migraine headache. Co-morbidity was evaluated using electronic health records obtained from the PennOmics database comprising>1 million patient entries. Genetic co-heritability and causality via MR was assessed using data from the International Headache Consortium (23,285 cases, 95,425 controls) and circulating serum calcium levels (39,400 subjects). We observed co-occurrence of migraine and hypercalcaemia ICD-9 diagnoses (OR = 1.58, P = 4 x 10-(13)), even after inclusion of additional risk factors for migraine (OR = 1.23, P = 2 x 10 -(3)). Second, we observed co-heritability (r(g) =0.191, P = 0.03) between serum calcium and migraine headache, indicating that these traits have a genetic basis in common. Finally, we found that elevation of serum calcium levels by 1 mg/dl resulting from our genetic score was associated with an increase in risk of migraine (OR = 1.80, 95% CI: 1.31-2.46, P = 2.5 x 10 -(4)), evidence supporting a causal hypothesis. We also present multiple MR sensitivity analyses in support of this central finding. Our results provide evidence that hypercalcaemia is comorbid with migraine headache diagnoses, and that genetically elevated serum calcium over lifetime appears to increase risk for migraine. Further studies will be required to understand the biologicalmechanism, pathways, and clinical implication for riskmanagement.Peer reviewe

Genome-wide association studies of metabolites in Finnish men identify disease-relevant loci

The Finnish population is enriched for genetic variants which are rare in other populations. Here, the authors find new genetic loci associated with 1391 circulating metabolites in 6136 Finnish men, demonstrating that metabolite genetic associations can help elucidate disease mechanisms. Few studies have explored the impact of rare variants (minor allele frequency < 1%) on highly heritable plasma metabolites identified in metabolomic screens. The Finnish population provides an ideal opportunity for such explorations, given the multiple bottlenecks and expansions that have shaped its history, and the enrichment for many otherwise rare alleles that has resulted. Here, we report genetic associations for 1391 plasma metabolites in 6136 men from the late-settlement region of Finland. We identify 303 novel association signals, more than one third at variants rare or enriched in Finns. Many of these signals identify genes not previously implicated in metabolite genome-wide association studies and suggest mechanisms for diseases and disease-related traits.Peer reviewe