Genetics of migraine and pharmacogenomics: some considerations

Migraine is a complex disorder caused by a combination of genetic and environmental factors

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

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

Genome-wide association analysis identifies susceptibility loci for migraine without aura

peer reviewedMigraine without aura is the most common form of migraine, characterized by recurrent disabling headache and associated autonomic symptoms. To identify common genetic variants associated with this migraine type, we analyzed genome-wide association data of 2,326 clinic-based German and Dutch individuals with migraine without aura and 4,580 population-matched controls. We selected SNPs from 12 loci with 2 or more SNPs associated with P values of <1 x 10(-5) for replication testing in 2,508 individuals with migraine without aura and 2,652 controls. SNPs at two of these loci showed convincing replication: at 1q22 (in MEF2D; replication P = 4.9 x 10(-4); combined P = 7.06 x 10(-11)) and at 3p24 (near TGFBR2; replication P = 1.0 x 10(-4); combined P = 1.17 x 10(-9)). In addition, SNPs at the PHACTR1 and ASTN2 loci showed suggestive evidence of replication (P = 0.01; combined P = 3.20 x 10(-8) and P = 0.02; combined P = 3.86 x 10(-8), respectively). We also replicated associations at two previously reported migraine loci in or near TRPM8 and LRP1. This study identifies the first susceptibility loci for migraine without aura, thereby expanding our knowledge of this debilitating neurological disorder

Animal Visibility and and Equality in Liberal Democratic States

Animal welfare legislation does not consistently protect all nonhuman animals against all harms under all circumstances. Through an analysis of current legislative arrangements and the origins of animal protection law, and an examination of popular attitudes towards animal cruelty, this study seeks to comment on the role of visibility in informing the level and type of state-sponsored interest protection an animal receives. It is argued that different types of animals enjoy different levels of visibility and that an animal’s level of visibility influences the extent to which the state is willing to intervene to protect the animal from harm. These findings are significant because the highly politicised nature of the lives of many nonhuman animals raises questions about the appropriateness of an animal welfare legislative regime which is at once biased and which also tends to favour those animals who are most readily visible. It is argued that the practice of regulating animal welfare by use of legislative instruments which are inconsistent is problematic from the perspective of liberal principles because liberalism places a heavy emphasis on the concept of equality. Similarly, the practice of preferential treatment for the most visible is not consistent with democratic values because it removes citizens from the process of establishing agreed-upon standards for animal protection. In conclusion, it is argued that because some animals have been effectively drawn into the liberal democratic political landscape, the principle of equitable treatment should be applied to the manner in which the state regulates animal use. Such an approach would mean that animal use would be regulated according to the same values that are applied to other areas of political society. It would also have the effect of establishing what the community views as the appropriate level of nonhuman animal interest protection, by challenging the existence of a double standard predicated on the principle of low visibility

Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families (vol 98, pg 743, 2018)

Paroxysmal Cerebral Disorder