Rare risk variants associate with epigenetic dysregulation in migraine

Migraine has a heritability of up to 65%. Genome-wide association studies (GWAS) on migraine have identified 123 risk loci, explaining only 10.6% of migraine heritability. Thus, there is a considerable genetic component not identified with GWAS. Further, the causality of the identified risk loci remains inconclusive. Rare variants contribute to the risk of migraine but GWAS are often underpowered to detect these. Whole genome sequencing is reliable for analyzing rare variants but is not frequently used in large-scale. We assessed if rare variants in the migraine risk loci associated with migraine. We used a large cohort of whole genome sequenced migraine patients (1,040 individuals from 155 families). The findings were replicated in an independent case-control cohort (2,027 migraine patients, 1,650 controls). We found rare variants (minor allele frequency<0.1%) associated with migraine in a Polycomb Response Element in the ASTN2 locus. The association was independent of the GWAS lead risk variant in the locus. The findings place rare variants as risk factors for migraine. We propose a biological mechanism by which epigenetic regulation by Polycomb Response Elements plays a crucial role in migraine etiology.

MARC1 p.A165T variant is associated with decreased markers of liver injury and enhanced antioxidant capacity in autoimmune hepatitis

The clinical picture of autoimmune hepatitis (AIH) varies markedly between patients, potentially due to genetic modifiers. The aim of this study was to evaluate genetic variants previously associated with fatty liver as potential modulators of the AIH phenotype. The study cohort comprised 313 non-transplanted adults with AIH. In all patients, the MARC1 (rs2642438), HSD17B13 (rs72613567), PNPLA3 (rs738409), TM6SF2 (rs58542926), and MBOAT7 (rs641738) variants were genotyped using TaqMan assays. Mitochondrial damage markers in serum were analyzed in relation to the MARC1 variant. Carriers of the protective MARC1 allele had lower ALT and AST (both P < 0.05). In patients treated for AIH for ≥ 6 months, MARC1 correlated with reduced AST, ALP, GGT (all P ≤ 0.01), and lower APRI (P = 0.02). Patients carrying the protective MARC1 genotype had higher total antioxidant activity (P < 0.01) and catalase levels (P = 0.02) in serum. The PNPLA3 risk variant was associated with higher MELD (P = 0.02) in treated patients, whereas MBOAT7 increased the odds for liver cancer (OR = 3.71). None of the variants modulated the risk of death or transplantation. In conclusion, the MARC1 polymorphism has protective effects in AIH. Genotyping of MARC1, PNPLA3, and MBOAT7 polymorphisms might help to stratify patients with AIH.

Hippocampal Volume Is Smaller In Female Double Carriers Of Two Strongest AD Genetic Risk Factors

Genetic risk factors for Alzheimer’s disease (AD) may facilitate AD-related changes in the brain long before AD clinical manifestation. While APOE4 was linked to a reduced hippocampal volume (HV) in a number of studies, the impact of rs2075650, another polymorphism strongly associated with AD, on HV is less clear. The rs2075650 (in TOMM40) is only in moderate to low LD with APOE4, and may have independent effects on HV or interact with APOE4. We studied associations of rs2075650 (G allele, risk factor for AD), rs429358 (C allele, proxy for APOE4), and their combinations, with right HV measured by MRI, among 10,738 women and 9,775 men aged 60-75, from UK Biobank. We found that right HV was significantly (p&lt;0.02) smaller in women who carry both AD risk variants (rs2075650(G) and rs429358(C)), than in non-carriers of both of these variants, while having only one risk variant (G or C) didn’t clearly affect HV. The studied associations didn’t reach statistical significance in men. Our results suggest that rs2075650(G) and rs429358(C) may contribute synergistically to a reduction in hippocampus volume, in females only, and support the role of interactions between genetic risk factors for AD in sex differences in preclinical biomarkers of AD pathology.

Identification of Atrial Fibrillation Risk Variant RS2200733 In Indian Young Adult Population

Atrial fibrillation (AF) is a common cardiac arrhythmia that affects millions of people. a substantial genetic contribution to AF has been identified by number of studies over the years. The SNP that is often linked with genetic predisposition to AF is rs2200733 located in the intergenic region close to PITX2 gene which is implicated in cardiac structure and function. rs2200733 is commonly observed in major global populations. Our study aimed to establish the prevalence of this important SNP among young healthy adults in order to assess the risk of genetic susceptibility which could culminate into AF later in life. The study identified a substantial frequency of rs2200733 in Indian population at 21%.

Differential Stimulation of Pluripotent Stem Cell-Derived Human Microglia Leads to Exosomal Proteomic Changes Affecting Neurons

Microglial exosomes are an emerging communication pathway, implicated in fulfilling homeostatic microglial functions and transmitting neurodegenerative signals. Gene variants of triggering receptor expressed on myeloid cells-2 (TREM2) are associated with an increased risk of developing dementia. We investigated the influence of the TREM2 Alzheimer’s disease risk variant, R47Hhet, on the microglial exosomal proteome consisting of 3019 proteins secreted from human iPS-derived microglia (iPS-Mg). Exosomal protein content changed according to how the iPS-Mg were stimulated. Thus lipopolysaccharide (LPS) induced microglial exosomes to contain more inflammatory signals, whilst stimulation with the TREM2 ligand phosphatidylserine (PS+) increased metabolic signals within the microglial exosomes. We tested the effect of these exosomes on neurons and found that the exosomal protein changes were functionally relevant and influenced downstream functions in both neurons and microglia. Exosomes from R47Hhet iPS-Mg contained disease-associated microglial (DAM) signature proteins and were less able to promote the outgrowth of neuronal processes and increase mitochondrial metabolism in neurons compared with exosomes from the common TREM2 variant iPS-Mg. Taken together, these data highlight the importance of microglial exosomes in fulfilling microglial functions. Additionally, variations in the exosomal proteome influenced by the R47Hhet TREM2 variant may underlie the increased risk of Alzheimer’s disease associated with this variant.

Methodological Case Study Approach for Detecting Business Model Enablers in Copycat Ventures

The approach of copying business models to create a successful company is discredited as non-innovative and propagated as a low-risk variant of entrepreneurship although a simple so-called copycat would only increase competition in the market and not guarantee success. Hence, the question of which characteristics of a business model enable success of such developed businesses arises. This paper presents a methodical approach to the analysis of enablers in business models based on case study research. With the validation of the approach using the business model canvas, a study among e-commerce companies is conducted, and success factors for copycats are identified. The methodological concept can also be applied to other industries and can deliver detailed results using more complex business model tools.