Potential Loci Research Articles

Association between chronic tinnitus and brain-derived neurotrophic factor antisense RNA polymorphisms linked to the Val66Met polymorphism in BDNF

Tinnitus is the sound heard in the ear or head of a person in the absence of external stimuli. Its etiopathogenesis is still not fully understood and the etiological causes responsible for tinnitus are quite variable. Brain-derived neurotrophic factor (BDNF) is one of the key neurotrophic factors in the growth, differentiation, and survival of neurons and in the developing auditory pathway, including the inner ear sensory epithelium. The regulation of BDNF gene is known to be managed by BDNF antisense (BDNF-AS) gene. BDNF-AS is located downstream of the BDNF gene and transcribes a long non-coding RNA. Inhibition of BDNF-AS upregulates BDNF mRNA, which increases protein levels and stimulates neuronal development and differentiation. Thus, BDNF and BDNF-AS both may play roles in the auditory pathway. Polymorphisms in both genes may have impact on hearing performance. A link was suggested between tinnitus and BDNF Val66Met polymorphism. However, there is no study questioning the relationship of tinnitus with BDNF-AS polymorphisms linked with BDNF Val66Met polymorphism. Therefore, this study aimed to scrutinize the role of BDNF-AS polymorphisms showing linkage with the BDNF Val66Met polymorphism in the course of tinnitus pathophysiology. Six BDNF-AS polymorphisms were analyzed on the tinnitus patients (n = 85) and the control subjects (n = 60) by Fluidigm Real-Time PCR using the Fluidigm Biomark microfluidic platform. When BDNF-AS polymorphisms were compared between the groups in terms of genotype and gender distribution, statistically significant differences were detected in rs925946, rs1519480, and rs10767658, polymorphisms (p less than 0.05). When the polymorphisms were compared by the duration of tinnitus, significant differences were found in rs925946, rs1488830, rs1519480, and rs10767658 polymorphisms (p less than 0.05). According to genetic inheritance model analysis, 2.33 and 1.53-fold risks were found for the rs10767658 polymorphism in the recessive and the additive models, respectively. For the rs1519480 polymorphism, a 2.25 fold risk was observed in the additive model. For the rs925946 polymorphism, 2.44 fold protective effect in dominant model, and 0.62 fold risk was found in the additive model. In conclusion, four of the polymorphisms in BDNF-AS gene (rs955946, rs1488830, rs1519480, and rs10767658) are potential gene loci that may play a role in the auditory pathway and affect auditory performance.

Ocean Bottom Seismometers in Suruga Bay reveal a shear zone inside the Philippine Sea plate slab

Suruga Bay lies along the Tokai segment of the Nankai-trough, which last ruptured in the 1854 M8.4 Ansei-Tokai Earthquake, making it a potential locus for the next major earthquake on the Nankai-trough. Moderate size earthquakes have occurred in the Suruga Trough axial region (M6.5 in 2009 and M6.2 in 2011) that resulted in a prominent excitation of seismicity. Unfortunately, our ability to accurately locate these events is hampered by a sparse routine seismic observation network around the bay. In order to improve location accuracy, a total of 2 sets of 7 OBSs were deployed inside Suruga Bay, 6 from the spring of 2017, and an additional OBS from spring 2019. By combining the data from our OBS stations with that of existing land-based stations surrounding Suruga Bay, we were able to accurately relocate the observed seismic activity inside the Philippine Sea plate (PHS). Our combined processing revealed a 25° northwest-dipping 2–5 km wide zone on which the regional seismic activity occurs. Overall, seismic activity is observed to be 5–10 km shallower than previously determined from routine network data alone. A striking feature of the analyzed activity is the presence of a prominent strike-slip component in the focal mechanisms, which exhibit P-axes almost exclusively oriented towards the north. Furthermore, taking into consideration the apparent difference in the direction of the P-axis of the stress field to the calculated sense of movement of Izu peninsula by GNSS data, and the ongoing internal deformation observed by geodetic and geological data, we propose the existence of a shear zone inside the subducting PHS starting from the southern tip of Izu Peninsula and extending across the bay under Shizuoka city. This zone of strain partitioning acts as a buffer between the northward-colliding Izu Peninsula and the northwest-directed subduction of the PHS observed by GNSS.

Role of Delta/Notch-like EGF-related receptor in blood glucose homeostasis.

Cell-cell interactions are necessary for optimal endocrine functions in the pancreas. β-cells, characterized by the expression and secretion of the hormone insulin, are a major constituent of functional micro-organs in the pancreas known as islets of Langerhans. Cell-cell contacts between β-cells are required to regulate insulin production and glucose-stimulated insulin secretion, which are key determinants of blood glucose homeostasis. Contact-dependent interactions between β-cells are mediated by gap junctions and cell adhesion molecules such as E-cadherin and N-CAM. Recent genome-wide studies have implicated Delta/Notch-like EGF-related receptor (Dner) as a potential susceptibility locus for Type 2 Diabetes in humans. DNER is a transmembrane protein and a proposed Notch ligand. DNER has been implicated in neuron-glia development and cell-cell interactions. Studies herein demonstrate that DNER is expressed in β-cells with an onset during early postnatal life and sustained throughout adulthood in mice. DNER loss in adult β-cells in mice (β-Dner cKO mice) disrupted islet architecture and decreased the expression of N-CAM and E-cadherin. β-Dner cKO mice also exhibited impaired glucose tolerance, defects in glucose- and KCl-induced insulin secretion, and decreased insulin sensitivity. Together, these studies suggest that DNER plays a crucial role in mediating islet cell-cell interactions and glucose homeostasis.

Shared genetics of migraine with irritable bowel syndrome, peptic ulcer, gastric reflux, diverticular disease, and autoimmune GI disorders (S19.005)

<h3>Objective:</h3> To investigate potential genetic relationships and therefore biology that may underlie comorbidity of migraine and several gastrointestinal (GI) disorders. <h3>Background:</h3> Individuals who experience migraine have elevated risk of irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), and peptic ulcer (PUD), but not autoimmune GI disorders. Moreover, migraine treatments targeting CGRP and serotonin pathways are also effective for IBS. The extent to which genetics informs and extends these risk and treatment relationships is unknown. <h3>Design/Methods:</h3> Analysis compared summary statistics from large-scale genome-wide association studies for migraine to those for IBS, PUD, GERD, diverticular disease (DD), and autoimmune GI disorders (inflammatory bowel disease, Crohn’s disease, and ulcerative colitis). Shared genetics was investigated by evaluating pairwise global and local genetic correlations, identifying potential shared candidate loci, inferring tissues relevant to genetic overlaps, and assessing potential causal relationships with genetic instrumental analysis. <h3>Results:</h3> Genome-wide genetic correlation was strong for migraine with IBS (r_g=0.37), GERD (r_g=0.34), and PUD (r_g=0.29) (all p&lt;5×10⁻⁹), attenuated with DD (r_g=0.18, p=7×10⁻⁷), and null with autoimmune GI disorders. The overlaps implicated shared functions of cardiovascular tissues for IBS and of the central nervous system for PUD and GERD. Locally, there were 10 novel loci among those shared with migraine: three loci for IBS; four different loci for GERD or PUD; and seven different loci for DD that partially overlapped nine loci for inflammatory disorders. However, at loci encoding targets of migraine therapeutics, correlation was only nominally significant (<i>CALCA</i>) or null (<i>HTR1F</i>). The local genetic signals of migraine with IBS, GERD, and PUD implicated functions of cerebellar, pituitary, and thyroid tissues. Genetic causal inference supported GERD, PUD, and DD as potential causes of migraine but not vice versa. <h3>Conclusions:</h3> Migraine shares genetics with IBS, GERD, PUD, and DD, although in distinct ways, thereby identifying novel loci, causal pathways, and potentially, tissues with shared biological functions. <b>Disclosure:</b> Daniel Chasman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Takeda. Daniel Chasman has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Amgen. Daniel Chasman has received research support from Pfizer. Daniel Chasman has received intellectual property interests from a discovery or technology relating to health care. Prof. Guo has nothing to disclose. Dr. Chan has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer Pharma AG. Dr. Chan has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pfizer Inc. Dr. Chan has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Gastroenterology. Dr. Chan has received personal compensation in the range of $100,000-$499,999 for serving as an Expert Witness for Boehringer Ingelheim. The institution of Dr. Chan has received research support from Zoe Ltd. The institution of Dr. Chan has received research support from Pfizer Inc. Dr. Staller has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GI Supply. Dr. Staller has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Dr. Staller has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Anji. The institution of Dr. Staller has received research support from Urovant. The institution of Dr. Staller has received research support from Ironwood. Dr. Rist has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Heart Association. The institution of Dr. Rist has received research support from National Institutes of Health. The institution of Dr. Rist has received research support from Biogen, Inc. The institution of Dr. Rist has received research support from Brigham and Women’s Hospital.

Validation of a male-specific DNA marker confirms XX/XY-type sex determination in several Hungarian strains of African catfish (Clarias gariepinus)

African catfish (Clarias gariepinus) is a promising food fish species with significant potential and growing mass of production in freshwater aquaculture. Male African catfish possess improved production characteristics over females, therefore the use of monosex populations could be advantageous for aquaculture production. However, our knowledge about the sex determination mechanism of this species is still limited and controversial. A previously isolated male-specific DNA marker (CgaY1) was validated using offspring groups from targeted crosses (n = 630) and it was found to predict the sex of 608 individuals correctly (96.43% accuracy). Using the proportion of recombinants, we estimated the average genetic distance between the potential sex determination locus and the sex-specific marker to be 3.57 cM. As an earlier study suggested that both XX/XY and ZZ/ZW systems coexist in this species, we tested the applicability of their putative ‘moderately sex-linked loci’ and found that no sex-specific amplification could be detected for any of them. In addition, temperature-induced masculinization suggested by others was also tested, but no such effect was detected in our stocks when the published parameters were used for heat treatment. Altogether, our results support an exclusive XX/XY sex determination system in our African catfish stock and indicate a good potential for the future use of this male-specific DNA marker in research and commercial production.

Gene-specific silencing of SlPL16, a pectate lyase coding gene, extends the shelf life of tomato fruit

Pectate lyase plays an important role in fruit development and ripening. Although earlier studies showed SlPL, a pectate lyase encoding gene, functions dominantly in tomato fruit softening, the functions of many other pectate lyase encoding genes involved in tomato fruit development and softening remain unknown. Here, gene-specific silencing of SlPL16 (Solyc06g083580) by RNA interference (RNAi) resulted in reduced pectate lyase enzyme activity, pericarp thickness, and soluble sugar content, and increased both the firmness and shelf life of tomato fruit. Through microscopic observation, it was found that the SlPL16-RNAi pericarp had reduced cell size, in comparison to the wild-type (WT). Moreover, gene silencing of SlPL16 resulted in the down-regulation of genes involved in cell wall degradation and pectin synthesis at various fruit developmental stages. Together, these results indicate that SlPL16 provides an important supplement of pectate lyase activity in tomato fruit softening, along with a fundamental role in cell expansion during early fruit development. Additionally, this study provides a potential gene locus in genetic engineering to improve fruit storage tolerance.

Genetic Mapping and QTL Analysis of Fruit Traits in Melon (Cucumis melo L.).

Melon (Cucumis melo L.) is an important horticultural cash crop and its quality traits directly affect consumer choice and market price. These traits are controlled by genetic as well as environmental factors. In this study, a quantitative trait locus (QTL) mapping strategy was used to identify the potential genetic loci controlling quality traits of melons (i.e., exocarp and pericarp firmness and soluble solid content) based on newly derived whole-genome single nucleotide polymorphism-based cleaved amplified polymorphic sequence (SNP-CAPS) markers. Specifically, SNPs of two melon varieties, M4-5 and M1-15, as revealed by whole-genome sequencing, were converted to the CAPS markers, which were used to construct a genetic linkage map comprising 12 chromosomes with a total length of 1414.88 cM, in the F2 population of M4-5 and M1-15. The six identified QTLs included: SSC6.1 and SSC11.1 related to soluble solid content; EF12.1 associated with exocarp firmness; and EPF3.1, EPF3.2 and EPF7.1 related to edible pericarp firmness. These genes were located on five chromosomes (3, 6, 7, 11, and 12) in the flanking regions of the CAPS markers. Moreover, the newly developed CAPS markers will be useful in guiding genetic engineering and molecular breeding in melon.

Integrative analyses of biomarkers and pathways for diabetic nephropathy.

Background: Diabetic nephropathy (DN) is a widespread diabetic complication and a major cause of terminal kidney disease. There is no doubt that DN is a chronic disease that imposes substantial health and economic burdens on the world's populations. By now, several important and exciting advances have been made in research on etiopathogenesis. Therefore, the genetic mechanisms underlying these effects remain unknown. Methods: The GSE30122, GSE30528, and GSE30529 microarray datasets were downloaded from the Gene Expression Omnibus database (GEO). Analyses of differentially expressed genes (DEGs), enrichment of gene ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) were performed. Protein-protein interaction (PPI) network construction was completed by the STRING database. Hub genes were identified by Cytoscape software, and common hub genes were identified by taking intersection sets. The diagnostic value of common hub genes was then predicted in the GSE30529 and GSE30528 datasets. Further analysis was carried out on the modules to identify transcription factors and miRNA networks. As well, a comparative toxicogenomics database was used to assess interactions between potential key genes and diseases associated upstream of DN. Results: Samples from 19 DNs and 50 normal controls were identified in the GSE30122 dataset. 86 upregulated genes and 34 downregulated genes (a total of 120 DEGs). GO analysis showed significant enrichment in humoral immune response, protein activation cascade, complement activation, extracellular matrix, glycosaminoglycan binding, and antigen binding. KEGG analysis showed significant enrichment in complement and coagulation cascades, phagosomes, the Rap1 signaling pathway, the PI3K-Akt signaling pathway, and infection. GSEA was mainly enriched in the TYROBP causal network, the inflammatory response pathway, chemokine receptor binding, the interferon signaling pathway, ECM receptor interaction, and the integrin 1 pathway. Meanwhile, mRNA-miRNA and mRNA-TF networks were constructed for common hub genes. Nine pivotal genes were identified by taking the intersection. After validating the expression differences and diagnostic values of the GSE30528 and GSE30529 datasets, eight pivotal genes (TYROBP, ITGB2, CD53, IL10RA, LAPTM5, CD48, C1QA, and IRF8) were finally identified as having diagnostic values. Conclusion: Pathway enrichment analysis scores provide insight into the genetic phenotype and may propose molecular mechanisms of DN. The target genes TYROBP, ITGB2, CD53, IL10RA, LAPTM5, CD48, C1QA, and IRF8 are promising new targets for DN. SPI1, HIF1A, STAT1, KLF5, RUNX1, MBD1, SP1, and WT1 may be involved in the regulatory mechanisms of DN development. Our study may provide a potential biomarker or therapeutic locus for the study of DN.

Comparative transcriptome analysis revealed genes involved in the sexual size dimorphisms and expressed sequence tag-Simple Sequence Repeat loci validation in Odorrana graminea

Sexual size dimorphism (SSD) is widespread among animals and is characterized by differences in body size between sexes. Previous studies suggested SSD might reflect the adaptations of particular sexes to their specific reproductive or ecological roles. The large green cascade frogs (Odorrana graminea) exhibit obvious SSD that females are nearly twice the body size of males. However, the molecular mechanisms underlying SSD of O. graminea are still unknown. In the present study, we first obtained nearly 5 Gb of the transcriptome data through Illumina sequencing, and the de novo transcriptome assembly produced 189,868 unigenes of O. graminea. A total of 774 significantly sex-differentially expressed genes (DEGs) were identified. Of which, 436 DEGs showed significantly higher expression levels in females than those in males, whereas 338 DEGs showed significantly lower expression in females than those in males. We also found 10 sex-differentially expressed genes related to energy metabolism between sexes of O. graminea, and these DEGs were related to the estrogen signaling pathway, oxidative phosphorylation, fatty acid biosynthesis, gastric acid secretion, and nitrogen metabolism. We found that the differences in energy metabolism and steroid hormone synthesis might be the main driving force leading to the sexual growth dimorphism of O. graminea. In addition, a total of 63,269 potential EST-SSR loci and 4,669 EST-SSR loci were detected and validated in different populations of O. graminea and other species within Odorrana. The assembled transcriptome will facilitate functional genomic studies of O. graminea and the developed EST-SSR markers will contribute to the population genetics of the species within Odorrana. The sex-differentially expressed genes involved in energy metabolism might provide insights into the genetic mechanisms underlying the SSD of O. graminea.

Differential expression and significance of 5-hydroxymethylcytosine modification in hepatitis B virus carriers and patients with liver cirrhosis and liver cancer.

The relationship between hepatitis B surface antigen (HBsAg)-positive carrier status and liver cancer has been extensively studied. However, the epigenetic changes that occur during progression from HBsAg-positive carrier status or cirrhosis to liver cancer are unknown. The epigenetic modification of DNA hydroxymethylation is critical in tumor development. Further, 5-hydroxymethylcytosine (5hmC) is an important base for DNA demethylation and epigenetic regulation. It is also involved in the assembly of chromosomes and the regulation of gene expression. However, the mechanism of action of 5hmC in HBsAg-positive carriers or patients with cirrhosis who develop liver cancer has not been fully elucidated. To investigate the possible epigenetic mechanism of HBsAg-positive carriers and hepatocellular carcinoma (HCC) progression from cirrhosis. Forty HBsAg-positive carriers, forty patients with liver cirrhosis, and forty patients with liver cancer admitted to the First People's Hospital of Yongkang between March 2020 and November 2021 were selected as participants. Free DNA was extracted using a cf-DNA kit. cfDNA was extracted by 5hmC DNA sequencing for principal component analysis, the expression profiles of the three groups of samples were detected, and the differentially expressed genes (DEGs) modified by hydroxymethylation were screened. Bioinformatic analysis was used to enrich DEGs, such as in biological pathways. A total of 16455 hydroxymethylated genes were identified. Sequencing results showed that 32 genes had significant 5hmC modification differences between HBsAg carriers and liver cancer patients, of which 30 were upregulated and 2 downregulated in patients with HCC compared with HBsAg-positive carriers. Significant 5hmC modification differences between liver cirrhosis and liver cancer patients were identified in 20 genes, of which 17 were upregulated and 3 were downregulated in patients with HCC compared with those with cirrhosis. These genes may have potential loci that are undiscovered or unelucidated, which contribute to the development and progression of liver cancer. Analysis of gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes showed that the major signaling pathways involved in the differential genes were biliary secretion and insulin secretion. The analysis of protein interactions showed that the important genes in the protein-protein interaction network were phosphoenolpyruvate carboxykinase and solute carrier family 2. The occurrence and development of liver cancer involves multiple genes and pathways, which may be potential targets for preventing hepatitis B carriers from developing liver cancer.

Cross-cancer pleiotropic analysis identifies three novel genetic risk loci for colorectal cancer.

To understand the shared genetic basis between colorectal cancer (CRC) and other cancers and identify potential pleiotropic loci for compensating the missing genetic heritability of CRC. We conducted a systematic genome-wide pleiotropy scan to appraise associations between cancer-related genetic variants and CRC risk among European populations. Single nucleotide polymorphism (SNP)-set analysis was performed using data from the UK Biobank and the Study of Colorectal Cancer in Scotland (10 039 CRC cases and 30 277 controls) to evaluate the overlapped genetic regions for susceptibility of CRC and other cancers. The variant-level pleiotropic associations between CRC and other cancers were examined by CRC genome-wide association study meta-analysis and the pleiotropic analysis under composite null hypothesis (PLACO) pleiotropy test. Gene-based, co-expression and pathway enrichment analyses were performed to explore potential shared biological pathways. The interaction between novel genetic variants and common environmental factors was further examined for their effects on CRC. Genome-wide pleiotropic analysis identified three novel SNPs (rs2230469, rs9277378 and rs143190905) and three mapped genes (PIP4K2A, HLA-DPB1 and RTEL1) to be associated with CRC. These genetic variants were significant expressions quantitative trait loci in colon tissue, influencing the expression of their mapped genes. Significant interactions of PIP4K2A and HLA-DPB1 with environmental factors, including smoking and alcohol drinking, were observed. All mapped genes and their co-expressed genes were significantly enriched in pathways involved in carcinogenesis. Our findings provide an important insight into the shared genetic basis between CRC and other cancers. We revealed several novel CRC susceptibility loci to help understand the genetic architecture of CRC.

Genetic susceptibility for schizophrenia after adjustment by genetic susceptibility for smoking: implications in identification of risk genes and genetic correlation with related traits.

Prevalence of smoking in schizophrenia (SCZ) is larger than in general population. Genetic studies provided some evidence of a causal effect of smoking on SCZ. We aim to characterize the genetic susceptibility to SCZ affected by genetic susceptibility to smoking. Multi-trait-based conditional and joint analysis was applied to the largest European SCZ genome-wide association studies (GWAS) to remove genetic effects on SCZ driven by smoking, estimated by generalized summary data-based Mendelian randomization. Enrichment analysis was performed to compare original v. conditional GWAS. Change in genetic correlation between SCZ and relevant traits after conditioning was assessed. Colocalization analysis was performed to identify specific loci confirming general findings. Conditional analysis identified 19 new risk loci for SCZ and 42 lost loci whose association with SCZ may be partially driven by smoking. These results were strengthened by colocalization analysis. Enrichment analysis indicated a higher association of differentially expressed genes at prenatal brain stages after conditioning. Genetic correlation of SCZ with substance use and dependence, attention deficit-hyperactivity disorder, and several externalizing traits significantly changed after conditioning. Colocalization of association signal between SCZ and these traits was identified for some of the lost loci, such as CHRNA2, CUL3, and PCDH7. Our approach led to identification of potential new SCZ loci, loci partially associated to SCZ through smoking, and a shared genetic susceptibility between SCZ and smoking behavior related to externalizing phenotypes. Application of this approach to other psychiatric disorders and substances may lead to a better understanding of the role of substances on mental health.

Potential loci and candidate genes associated with Vibrio anguillarum resistance in black rockfish (Sebastes schlegelii) revealed by BSA-seq analysis

Potential loci and candidate genes associated with Vibrio anguillarum resistance in black rockfish (Sebastes schlegelii) revealed by BSA-seq analysis

Interchromosomal linkage disequilibrium and linked fitness cost loci associated with selection for herbicide resistance.

The adaptation of weeds to herbicide is both a significant problem in agriculture and a model of rapid adaptation. However, significant gaps remain in our knowledge of resistance controlled by many loci and the evolutionary factors that influence the maintenance of resistance. Here, using herbicide-resistant populations of the common morning glory (Ipomoea purpurea), we perform a multilevel analysis of the genome and transcriptome to uncover putative loci involved in nontarget-site herbicide resistance (NTSR) and to examine evolutionary forces underlying the maintenance of resistance in natural populations. We found loci involved in herbicide detoxification and stress sensing to be under selection and confirmed that detoxification is responsible for glyphosate (RoundUp) resistance using a functional assay. We identified interchromosomal linkage disequilibrium (ILD) among loci under selection reflecting either historical processes or additive effects leading to the resistance phenotype. We further identified potential fitness cost loci that were strongly linked to resistance alleles, indicating the role of genetic hitchhiking in maintaining the cost. Overall, our work suggests that NTSR glyphosate resistance in I. purpurea is conferred by multiple genes which are potentially maintained through generations via ILD, and that the fitness cost associated with resistance in this species is likely a by-product of genetic hitchhiking.

A Genome-Wide Association Study of Dementia Using the Electronic Medical Record

Dementia is characterized as a decline in cognitive function, including memory, language and problem-solving abilities. In this paper, we conducted a Genome-Wide Association Study (GWAS) using data from the electronic Medical Records and Genomics (eMERGE) network. This study has two aims, (1) to investigate the genetic mechanism of dementia and (2) to discuss multiple p-value thresholds used to address multiple testing issues. Using the genome-wide significant threshold (p≤5×10−8), we identified four SNPs. Controlling the False Positive Rate (FDR) level below 0.05 leads to one extra SNP. Five SNPs that we found are also supported by QQ-plot comparing observed p-values with expected p-values. All these five SNPs belong to the TOMM40 gene on chromosome 19. Other published studies independently validate the relationship between TOMM40 and dementia. Some published studies use a relaxed threshold (p≤1×10−5) to discover SNPs when the statistical power is insufficient. This relaxed threshold is more powerful but cannot properly control false positives in multiple testing. We identified 13 SNPs using this threshold, which led to the discovery of extra genes (such as ATP10A-DT and PTPRM). Other published studies reported these genes as related to brain development or neuro-development, indicating these genes are potential novel genes for dementia. Those novel potential loci and genes may help identify targets for developing new therapies. However, we suggest using them with caution since they are discovered without proper false positive control.

Abstract WMP106: Sex-stratified Transethnic GWAS Meta-analysis Identifies Novel Candidates For Early Onset Ischemic Stroke

Background: Early onset ischemic stroke (IS) affects males and females unequally, but the etiologic background of the sex differences remains inadequately understood. We hypothesize that stratifying GWAS by sex provides an opportunity to 1) identify loci that shed light on mechanisms and pathways relevant to sex specific effects in IS and 2) discover novel IS loci. Methods: We performed a sex-stratified transethnic GWAS meta-analysis in 6,879 female IS cases and 11,264 male cases &lt; 60 years-old and &gt; 700,000 sex-matched controls from the Early Onset Stroke Genetics Consortium. We tested for difference (p-diff) between the men- and women-specific beta-estimates with corresponding standard errors using the t statistics. Results: We found genome-wide significant evidence for association (p &lt; 5 х 10 -8 ) at a locus near NYAP2 for females (chr2:225661726:C:CT, p = 2.11 х 10 -8 , OR = 1.38, p-diff = 1.69 х 10 -4 ) and in PIAS4 for males (chr19:4013652:C:CA, p = 6.29 х 10 -9 , OR = 0.85, p-diff = 0.02) in transethnic analysis. NYAP2 has previously shown suggestive evidence for association with early onset menopause. PIAS4 , a candidate gene for migraine, has shown sex-specific expression levels in migraine patients compared to controls. Additional loci with suggestive evidence (p &lt; 1 х 10 -6 ) for association in a sex-dependent manner included MMP1-MMP3 - MMP12 , a previously known stroke locus, for males (chr11:102822455:A:G, p = 3.99 х 10 -7 , OR = 1.17, p-diff = 0.02), and a novel stroke locus near TMX1 , a transmembrane platelet protein, for females (chr14:51193174:G:C, p = 4.15 х 10 -7 , OR = 1.76, p-diff = 4.08 х 10 -3 ). The known early onset IS locus ABO did not show evidence for sex-specific association despite suggestive association in the male stratified analysis (chr9:133274295:A:T, p = 3.15 х 10 -7 , OR = 1.17, p-diff = 0.81). Conclusions: We identified potential novel stroke loci and evidence for sex differences at other biologically relevant loci by stratifying GWAS by sex. To our knowledge, our cohort represents the largest early onset IS GWAS cohort to date. However, our findings require verification in large sample sizes and also evaluation in older onset IS. Sex-specific association analysis is a potentially useful tool for characterizing the genetic basis of early onset IS.

Genetics of osteonecrosis in children and adults with systemic lupus erythematosus.

Genetics plays an important role in SLE risk, as well as osteonecrosis (ON), a significant and often debilitating complication of SLE. We aimed to identify genetic risk loci for ON in people with childhood-onset (cSLE) and adult-onset (aSLE) SLE. We enrolled participants from two tertiary care centres who met classification criteria for SLE. Participants had prospectively collected clinical data and were genotyped on a multiethnic array. Un-genotyped single nucleotide polymorphisms (SNPs) were imputed, and ancestry was inferred using principal components (PCs). Our outcome was symptomatic ON confirmed by imaging. We completed time-to-ON and logistic regression of ON genome-wide association studies (GWASs) with covariates for sex, age of SLE diagnosis, five PCs for ancestry, corticosteroid use and selected SLE manifestations. We conducted separate analyses for cSLE and aSLE and meta-analysed results using inverse-variance weighting. Genome-wide significance was P < 5 × 10-8. The study included 940 participants with SLE, 87% female and 56% with cSLE. ON was present in 7.6% (n = 71). Median age of SLE diagnosis was 16.9 years (interquartile range [IQR]: 13.5, 29.3), with median follow-up of 8.0 years (IQR: 4.2, 15.7). Meta-GWAS of cSLE and aSLE time-to-ON of 4 431 911 SNPs identified a significant Chr.2 SNP, rs34118383 (minor allele frequency = 0.18), intronic to WIPF1 (hazard ratio = 3.2 [95% CI: 2.2, 4.8]; P = 1.0 × 10-8). We identified an intronic WIPF1 variant associated with a 3.2 times increased hazard for ON (95% CI: 2.2, 4.8; P = 1.0 × 10-8) during SLE follow-up, independent of corticosteroid exposure. The effect of the SNP on time-to-ON was similar in cSLE and aSLE. This novel discovery represents a potential ON risk locus. Our results warrant replication.

Polymorphism studies and candidate genes associated with litter size traits in Indonesian goats. a systematic review

Background: Litter size (LS) is a significant, challenging, and economical aspect of the goat industry in Indonesia. It is influenced by several different factors and genes; consequently, identifying potential genes and loci associated with litter size has become a genetic problem. Several genetic indicators have been found to be associated with litter size in goats. This has prompted the need to discuss candidate genes associated with litter size in goats in Indonesia. Methods: A systematic review was conducted using critical databases including ResearchGate, Google Scholar, PubMed, Google search engine and Science direct. There were any exclusion criteria, they were as follows: articles published in languages other than English, Conference papers, short communication papers and papers not related to animals. After reviewing the abstracts of 42 publications, the remaining 17 investigations were chosen for full paper evaluation. A further eight studies were removed after a comprehensive evaluation of the publications because they did not match our inclusion criteria. Results: These markers include growth differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15), bone morphogenetic protein receptor type IB (BMPR1B), and kisspeptin (KISS1). Single nucleotide polymorphisms in these genes contribute to the development of novel genetic markers that helps in the selection of goats with the most favorable genotypes for litter size. This type of genetic selection is more successful than the traditional way of selecting animals for reproductive traits, particularly litter size. Conclusions: As a result, this study summarizes the genetic impacts of polymorphisms in candidate genes associated with litter size features in Indonesian goats.

Fibril treatment changes protein interactions of tau and α-synuclein in human neurons

In several neurodegenerative disorders, the neuronal proteins tau and α-synuclein adopt aggregation-prone conformations capable of replicating within and between cells. To better understand how these conformational changes drive neuropathology, we compared the interactomes of tau and α-synuclein in the presence or the absence of recombinant fibril seeds. Human embryonic stem cells with an inducible neurogenin-2 transgene were differentiated into glutamatergic neurons expressing (1) WT 0N4R tau, (2) mutant (P301L) 0N4R tau, (3) WT α-synuclein, or (4) mutant (A53T) α-synuclein, each genetically fused to a promiscuous biotin ligase (BioID2). Neurons expressing unfused BioID2 served as controls. After treatment with fibrils or PBS, interacting proteins were labeled with biotin in situ and quantified using mass spectrometry via tandem mass tag labeling. By comparing interactions in mutant versus WT neurons and in fibril- versus PBS-treated neurons, we observed changes in protein interactions that are likely relevant to disease progression. We identified 45 shared interactors, suggesting that tau and α-synuclein function within some of the same pathways. Potential loci of shared interactions include microtubules, Wnt signaling complexes, and RNA granules. Following fibril treatment, physiological interactions decreased, whereas other interactions, including those between tau and 14-3-3 η, increased. We confirmed that 14-3-3 proteins, which are known to colocalize with protein aggregates during neurodegeneration, can promote or inhibit tau aggregation invitro depending on the specific combination of 14-3-3 isoform and tau sequence.

The Immune Ghosts of Pandemics Past

Klunk J, Vilgalys TP, Demeure CE, et al. Evolution of immune genes is associated with the Black Death. Nature 2022;611:312–319. Our immune system exists to protect us from the external environment and specifically from the complex threat posed by microbial pathogens. It is well-known that microbes have rapidly evolved to either avoid, adapt, or co-opt host biology to survive and multiply. Conversely, infectious diseases are postulated to provide a strong selective pressure driving human genetic evolution, with exposure to pathogens driving immune system adaptation. However, exactly how and which specific loci and related immune genes have changed in response to a specific pathogen and functionally connecting signatures to protection or susceptibility in human populations has proved to be a challenging problem. The recent study by Klunk et al sets out to identify specific genes that may have directly evolved because of pathogen-induced selective pressure. To achieve this, they looked back at one of the most devastating pandemics in human history—the Black Death caused by the bacteria Yersinia pestis, which killed an estimated 30%–50% of the population in Europe. In a remarkable feat of molecular archeology, the study team identified human remains in two closely related European populations, in London and Denmark, devastated by the Black Death. To identify potential loci significantly selected for by this devastating disease, they obtained DNA samples from people who died before, during, and after the pandemic at various burial sites around London. After targeted DNA sequencing of a curated list of immune system genes and loci along with neutral regions of the genome as reference, they first verified that the pandemic did indeed induce a significant selection pressure on the immune system, with the identification of 245 significantly altered variants. After further filtering based on allele frequency patterns before and after the pandemic, they identified 35 potential target loci. Using their identified Denmark cohort to cross-validate these variants they eventually settled on 4 significant and validated loci related to 6 immune genes that potentially conferred either susceptibility or protection from Y. pestis infection. Although all 4 loci suggested interesting potential functional consequences, the clearest candidate was a putatively protective variant close to the gene ERAP2, an aminopeptidase important for antigen presentation, viral clearance, and cytokine responses and a known risk factor for Crohn’s disease. The study team went on to conduct a series of functional studies in monocyte-derived macrophages comparing the ERAP2 gene haplotype selectively favored by Y. pestis infection against the alternative deleterious prepandemic haplotype. Here, they found that macrophages from individuals possessing the selected ERAP2 allele exhibit a different cytokine response to Y. pestis infection and are better able to limit replication in cells, providing a functional corelate for the evolved host response. This study represents a wonderful journey into the history of the biological “arms race” between our immune system and the microbial environment, identifying some the specific changes brought about by a global disease pandemic. These findings illuminate our understanding of our immune responses to pathogens and highlight the evolution of immune system components such as ERAP2, CTLA4, and ICOS, which are associated with chronic inflammatory diseases including Crohn’s disease and autoimmune enteropathies. The study is also highly prescient in the setting of the global SARS-CoV-2 pandemic, and the current, likely highly accelerated, evolution of our immune system.