East Asian Cohort Research Articles

Genomics yields biological and phenotypic insights into bipolar disorder.

Bipolar disorder is a leading contributor to the global burden of disease1. Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown2. We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.8 million controls), combining clinical, community and self-reported samples. We identified 298 genome-wide significant loci in the multi-ancestry meta-analysis, a fourfold increase over previous findings3, and identified an ancestry-specific association in the East Asian cohort. Integrating results from fine-mapping and other variant-to-gene mapping approaches identified 36 credible genes in the aetiology of bipolar disorder. Genes prioritized through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in cases with bipolar disorder4, highlighting convergence of common and rare variant signals. We report differences in the genetic architecture of bipolar disorderdepending on the source of patient ascertainment and on bipolar disorder subtype (type I or type II). Several analyses implicate specific cell types in the pathophysiology of bipolar disorder, including GABAergic interneurons and medium spiny neurons. Together, these analyses provide additional insights into the genetic architecture and biological underpinnings of bipolar disorder.

Causal associations between osteoporosis and HBV infection across Asian and European populations: evidence from Mendelian randomization and colocalization analysis

IntroductionClinical studies have demonstrated a potential association between chronic hepatitis caused by hepatitis B virus (HBV) infection and osteoporosis. However, the causal relationship between HBV infection and osteoporosis remains to be determined.MethodsWe investigated whether HBV infection is causally associated with osteoporosis using Mendelian randomization (MR) in East Asian and European populations, respectively. The data we utilized were obtained from the genome-wide association studies (GWAS) database. Various MR methods, including inverse variance weighted (IVW), MR Egger, weighted median, simple median and simple mode were employed to estimate the association between HBV infection and osteoporosis. Heterogeneity analysis and sensitivity tests were performed to ensure the robustness of the results. Bayesian co-localization (coloc) analysis was also applied to calculate the posterior probability of causal variants and to identify common genetic variants between HBV infection and osteoporosis.ResultsMR analysis indicated that HBV infection increased the risk of osteoporosis onset in two East Asian cohort (IVW, OR = 1.058, 95% CI = 1.021 to 1.097, P = 0.002 and OR = 1.067, 95% CI = 1.029 to 1.106, P < 0.001). However, a clear effect of genetic susceptibility to HBV on the enhanced risk of osteoporosis was not observed in two European cohort (IVW, OR = 1.000, 95% CI = 0.999 to 1.001, P = 0.171 and OR = 1.003, 95% CI = 0.981 to 1.025, P = 0.780). Additional MR methods and sensitivity analyses further validated the reliability and robustness of our results. Bayesian co-localization analysis revealed co-localization of HBV infection and osteoporosis on STAT4 at rs11889341based on East Asian GWAS data.ConclusionsOur study identified a causal relationship between HBV infection and osteoporosis in East Asian and European populations. These results provided strong evidence that HBV infection augmented the risk of developing osteoporosis in East Asian populations and provided novel therapeutic targets.

Intracerebral hemorrhage in CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small vessel disease caused by mutations in the NOTCH3 gene. This review highlights the increasing recognition of intracerebral hemorrhage (ICH) as a significant manifestation of CADASIL, often predominantly characterized by ischemic strokes and vascular dementia. Recent studies indicate that the prevalence of ICH in CADASIL patients ranges from 0.5% to 33.3%, the variability of which is mainly influenced by ethnicity. In East Asian cohorts, where specific NOTCH3 mutations like p.R544C and p.R75P are more prevalent and have been associated with a higher rate of ICH, suggesting a link between these mutations and the hemorrhagic risk. Hypertension, as with other etiologies of ICH, is a key risk factor in CADASIL patients, with 40-90% of those who experience ICH also having a history of hypertension. The presence of cerebral microbleeds (CMBs) and a high CMBs load are strongly associated with increased risk of ICH. Neuroimaging studies show that ICH in CADASIL patients predominantly occurs in the thalamus and basal ganglia. There is a notable spatial correlation between CMBs and subsequent ICH, suggesting that CMBs may serve as markers of microangiopathy in regions prone to vascular injury. CADASIL patients with ICH experience greater morbidity, higher mortality rates, and increased annual stroke recurrence risk compared to those with ischemic events. In summary, this review emphasizes the need for tailored management strategies that prioritize rigorous blood pressure control and the careful use of antithrombotic agents in CADASIL patients with a high burden of CMBs. By advancing our understanding of ICH in CADASIL, we aim to improve diagnostic and therapeutic approaches, ultimately enhancing patient outcomes and quality of life in this high-risk population.

Exploring the mediating role of blood metabolites in the relationship between gut microbiota and gastric cancer risk: a Mendelian randomization study.

Prior studies have established correlations between gut microbiota (GM) dysbiosis, circulating metabolite alterations, and gastric cancer (GC) risk. However, the causal nature of these associations remains uncertain. We utilized summary data from genome-wide association studies (GWAS) on GM (European, n=8,956), blood metabolites (European, n=120,241; East Asian, n=4,435), and GC (European, n=476,116; East Asian, n=167,122) to perform a bidirectional Mendelian randomization (MR) analysis, investigating the causal effects of GM and metabolites on GC risk. Additionally, we conducted mediation analysis (two-step MR) to identify potential metabolite mediators in the GM-GC relationship. We identified twelve negative and seven positive associations between specific GM taxa and GC risk. For blood metabolites, seven traits were found to be significantly associated with reduced GC risk in the European population, with these findings subsequently validated in the East Asian cohort. Three GM taxa showed potential causal associations with five metabolic traits: the Bacteroidia class and Bacteroidales order were positively correlated with five metabolites (all P < 0.013), while Bacteroides OTU97_27 exhibited a negative correlation with one metabolite (P = 0.007). Two-step MR analysis indicated that total lipids in intermediate-density lipoprotein (IDL), IDL particle concentration, phospholipids in medium low-density lipoprotein (LDL), phospholipids in small LDL, and free cholesterol in small LDL indirectly influenced the association between Bacteroidia class/Bacteroidales order and GC, with mediation proportions of 1.71% (P = 0.048), 1.69% (P = 0.048), 2.05% (P = 0.045), 1.85% (P = 0.048), and 1.99% (P = 0.045), respectively. The present study provides suggestive evidence of a causal relationship between specific GM, blood metabolites, and GC risk, potentially offering new insights into GC etiology.

Multiomic Mendelian Randomization Study Investigating the Impact of PCSK9 and HMGCR Inhibition on Type 2 Diabetes Across Five Populations.

The prevalence of type 2 diabetes (T2D) varies among populations of different race/ethnicity. The influence of genetically-proxied lipoprotein cholesterol (LDL-C) lowering through proprotein convertase subtilisin/kexin 9 (PCSK9) and HMG-CoA Reductase (HMGCR) on T2D in non-European populations is not well established.A drug-target Mendelian randomization (MR) approach was used to assess the effects of PCSK9 and HMGCR inhibition on T2D risk and glycemic traits in five populations: East Asian (EAS), South Asian (SAS), Hispanic (HISP), African (AFR), and European (EUR). Our study did not find relationships between genetically-proxied PCSK9 inhibition and T2D risk in EAS (odds ratio [OR]=1.02, [0.95-1.10]), SAS (OR=1.05, [0.97-1.14]), HISP (OR=1.03, [0.94-1.12]), or EUR (OR=1.04, [0.98-1.11]). However, in AFR, primary analyses suggested an increased risk of T2D due to PCSK9 inhibition (OR=1.53, [1.058-2.22], P-value=0.024), although this was not supported in sensitivity analyses. Genetically-proxied HMGCR inhibition was associated with an increased risk of T2D in SAS (OR=1.44, [1.30-1.61], P-value=9.8×10-12), EAS (OR=1.36, [1.22-1.51], P-value=4.2×10-10), and EUR (OR=1.52, [1.21-1.90], P-value=3.3×10-4). These results were consistent across various sensitivity analyses, including colocalization, indicating a robust finding. The findings indicate a neutral impact of long-term PCSK9 inhibition on T2D and glycemic markers in most non-European populations, with a potential increased risk in AFR cohorts. By contrast, HMGCR inhibition increased the risk of T2D in South Asian, East Asian, and European cohorts, underscoring the need to consider diversity in genetic research on metabolic diseases.

Transethnic analysis identifies SORL1 variants and haplotypes protective against Alzheimer's disease.

The SORL1 locus exhibits protective effects against Alzheimer's disease (AD) across ancestries, yet systematic studies in diverse populations are sparse. Logistic regression identified AD-associated SORL1 haplotypes in East Asian (N=5249) and European (N=8588) populations. Association analysis between SORL1 haplotypes and AD-associated traits or plasma biomarkers was conducted. The effects of non-synonymous mutations were assessed in cell-based systems. Protective SORL1 variants/haplotypes were identified in the East Asian and European populations. Haplotype Hap_A showed a strong protective effect against AD in East Asians, linked to less severe AD phenotypes, higher SORL1 transcript levels, and plasma proteomic changes. A missense variant within Hap_A, rs2282647-C allele, was linked to a lower risk of AD and decreased expression of a truncated SORL1 protein isoform. Our transethnic analysis revealed key SORL1 haplotypes that exert protective effects against AD, suggesting mechanisms of the protective role of SORL1 in AD. We examined the AD-protective mechanisms of SORL1 in the general population across diverse ancestral backgrounds by jointly analyzing data from three East Asian cohorts (ie, mainland China, Hong Kong, and Japan) and a European cohort. Comparative analysis unveiled key ethnic-specific SORL1 genetic variants and haplotypes. Among these, the SORL1 minor haplotype, Hap_A, emerged as the primary AD-protective factor in East Asians. Hap_A exerts significant AD-protective effects in both APOE ε4 carriers and non-carriers. SORL1 haplotype Hap_A is associated with cognitive function, brain volume, and the activity of specific neuronal and immune-related pathways closely connected to AD risk. Protective variants within Hap_A are linked to increased SORL1 expression in human tissues. We identified an isoform-specific missense variant in Hap_A that modifies the function and levels of a truncated SORL1 protein isoform that is poorly investigated.

Larger size of Conn's adenoma is associated with lower cure rates post adrenalectomy.

The cure for patients with primary hyperaldosteronism (PHA) secondary to solitary adrenal adenoma is adrenalectomy. We investigated the impact of size of Conns' tumour on hypertension resolution in a multi-ethnic South East Asian Cohort. Retrospective cohort study of patients who underwent surgery for PHA between January 2010 to December 2022 was performed. Clinicopathological parameters that included tumour size, blood pressure parameters, class and dosage of drugs, biochemical indices and details of surgery were collected. Cure of hypertension was defined as normal blood pressure post-adrenalectomy. Statistical significance was defined as a P value of < 0.05. 94 patients (40 female:54 male; 102 women; age 49.3 ± 11.8 years) with PHA were operated on laparoscopically (79 trans-abdominal and 15 retroperitoneal approach). Tumour size ranged from 0.4 to 4.6cm (mean 1.5 ± 0.6cm). Hypertension Grades were Grade 1 in 38 (40%), Grade 2 in 45 (48%) and Grade 3 in 11 (12%) patients. Patients were on a mean of 3 classes of drugs prior to surgery and this decreased to mean of 1 class of drug post adrenalectomy. All patients were rendered normokalaemic and overall cure of the patients from hypertension was 82.0%. Large adenoma (defined as greater than 1.5cm) resulting in a greater decrease in blood pressure (mean decrease of 32mmHg systolic, 15mmHg diastolic and MAP 20mmHg) in comparison to smaller adenomas (p = 0.003), but with lower cure rates of hypertension (p = 0.038). Large Conn's adenomas result in a greater reduction in blood pressure post-adrenalectomy but with decreased cure rates of hypertension compared to the small adenomas.

Hemorrhagic Moyamoya Angiopathy in European Patients.

Moyamoya angiopathy (MMA) is an important cause of juvenile stroke but an overall rare disease among European populations compared with East Asian cohorts. Consecutively, hemorrhagic MMA is described well in East Asian cohorts, but knowledge in non-Asian patients is limited. Literature suggests that disease presentation may vary between those cohorts, also including hemorrhage frequencies. Hence, this article aims to analyze hemorrhagic MMA in European patients. We screened for patients of European origin with MMA from a single-center consecutive database of a German hospital specialized on MMA. Those who had a record of intracranial hemorrhage were analyzed individually regarding the type of hemorrhage and use of antiplatelet therapy before and after bleeding onset. To identify associated factors of intracranial hemorrhage, an age- and sex-matched control group was identified from the pool of patients without a history of hemorrhage. Both groups had a comparable follow-up time and were compared in terms of disease presentation, therapeutic interventions, and imaging characteristics, using both univariate tests and multivariate logistic regression analysis. From a pool of 332 patients with MMA we identified 288 of European ancestry. From those, 36 had a record of intracranial hemorrhage (12.5%). Thirty-three patients presenting with 37 events were included for further analysis and case-control-comparison. Most events were intracerebral hemorrhage (n=20; 54%) and subarachnoid hemorrhage (n=11; 30%). 78% developed hemorrhage although no antiplatelet therapy was in use (n=29). Seven patients developed intracranial hemorrhage ipsilateral to prior bypass surgery (21%), while 29 of the control patients had a bypass surgery (88%; P=0.0001). There was no significant difference in terms of unilateral or bilateral disease type, history of hypertension, as well as imaging characteristics (high Suzuki stage and the presence of collateral pathways in conventional angiography, as well as ischemic defects and the presence of microbleeds on cerebral magnetic resonance imaging; P>0.05 in multivariate analysis, respectively). Bypass surgery was negatively associated with the development of intracranial hemorrhage in MMA in European patients. There was no difference in terms of a history of hypertension between groups, indicating that blood pressure is not the major contributor for rupture of fragile collateral vessels. The investigated imaging characteristics were not associated to hemorrhage onset and, therefore, are not suitable as a tool of screening for patients at risk.

Association between prostate cancer and susceptibility, hospitalization, and severity of COVID-19: Based on a Mendelian randomization study.

Several observational studies indicated a close association between prostate cancer and COVID-19. Nevertheless, whether there was a causal effect between them remained obscure. In this study, we aimed to detect the potential association between genetically determined prostate cancer and the risk of COVID-19. A bidirectional Mendelian randomization (MR) study was conducted to investigate the causal links between prostate cancer and COVID-19. Inverse variance weighted (IVW), MR-Egger, weighted median, weighted mode, and simple mode were used to estimate the causality. PIVW < 0.05 was considered statistically significant. The top single nucleotide polymorphisms associated with prostate cancer cases (n = 79,148) and COVID-19 cases (n = 54,071) were extracted from the summary genome-wide association study data obtained from a publicly available database. Cochran Q test was utilized to calculate the degree of heterogeneity. Additionally, we validated our findings in another replication cohort. In the forward MR study, the IVW method suggested no evidence for the causal effect of prostate cancer on COVID-19 susceptibility (OR = 1.00, 95%CI: 0.98-1.02, P = .978), COVID-19 hospitalization (OR = 1.05, 95%CI: 0.99-1.09, P = .054), and COVID-19 severity (OR = 1.03, 95%CI: 0.95-1.11, P = .453). Reverse MR analysis also showed no causal effect of COVID-19 diverse phenotypes on prostate cancer. Furthermore, the result of the East Asian cohort study was consistent with the European cohort. Sensitivity analysis showed no evidence of pleiotropy and heterogeneity. We did not discover genetic evidence to substantiate causal links between prostate cancer and COVID-19. Large-scale randomized controlled trials were required to enhance a more profound comprehension of this relationship in the future.

Genome-wide association study for metabolic syndrome reveals APOA5 single nucleotide polymorphisms with multilayered effects in Koreans

Background and purposeGenome-wide association studies (GWAS) of metabolic syndrome (MetS) have predominantly focused on non-Asian populations, with limited representation from East Asian cohorts. Moreover, previous GWAS analyses have primarily emphasized the significance of top single nucleotide polymorphisms (SNPs), poorly explaining other SNP signals in linkage disequilibrium. This study aimed to reveal the interaction between rs651821 and rs2266788, the principal variants of apolipoprotein A5 (APOA5), within the most significant loci identified through GWAS on MetS.MethodsGWAS on MetS and its components was conducted using the data from the Korean Genome and Epidemiology Study (KoGES) city cohort comprising 58,600 individuals with available biochemical, demographic, lifestyle factors, and the most significant APOA5 locus was analyzed further in depth.ResultsAccording to GWAS of MetS and its diagnostic components, a significant association between the APOA5 SNPs rs651821/rs2266788 and MetS/triglycerides/high-density lipoprotein phenotypes was revealed. However, a conditional analysis employing rs651821 unveiled a reversal in the odds ratio for rs2266788. Therefore, rs651821 and rs2266788 emerged as independent and opposing signals in the extended GWAS analysis, i.e., the multilayered effects. Further gene-environment interaction analyses regarding lifestyle factors such as smoking, alcohol consumption, and physical activity underscored these multilayered effects.ConclusionThis study unveils the intricate interplay between rs651821 and rs2266788 derived from MetS GWAS. Removing the influence of lead SNP reveals an independent protective signal associated with rs2266788, suggesting a multilayered effect between these SNPs. These findings underline the need for novel perspectives in future MetS GWAS.

Impaired glymphatic function as a biomarker for subjective cognitive decline: An exploratory dual cohort study.

Subjective cognitive decline (SCD) has been recognized as a potential risk stage for progression to Alzheimer's disease (AD), while glymphatic dysfunction is considered an important characteristic of AD. We hypothesize that glymphatic dysfunction occurs during the SCD stage, aiming to discover potential biomarkers for SCD. Participants from two independent studies, Sino Longitudinal Study on Cognitive Decline (SILCODE, n=654) and the Alzheimer's Disease Neuroimaging Initiative (ADNI, n=650), representing different ethnicities and disease stages, were included to assess glymphatic function using diffusion tensor image analysis along the perivascular space (DTI-ALPS). Abnormal glymphatic function occurs during the SCD stage, with the ALPS index demonstrating excellent classification performance for SCD and normal controls (area under the receiver operating characteristic curve [AUC]SILCODE=0.816, AUCADNI=0.797). Lower ALPS index indicates higher risk of cognitive progression, which is negatively correlated with Subjective Cognitive Decline Questionnaire 9 scores and amyloid positron emission tomography burden. Our study suggests the ALPS index has the potential to serve as a biomarker for SCD. Glymphatic function characterized by the analysis along the perivascular space (ALPS) index becomes abnormal in subjective cognitive decline (SCD), the earliest symptomatic manifestation and preclinical stage of Alzheimer's disease (AD). The ALPS index demonstrates excellent classification performance for SCD and normal controls in the East Asian and Western cohorts. Participants with a lower ALPS index show a higher risk of clinical progression. The ALPS index is closely associated with serval cognitive scales and amyloid beta burden.

Genetic and clinical characteristics of catecholaminergic polymorphic ventricular tachycardia in a Taiwanese nationwide cohort

BackgroundCatecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and lethal arrhythmia. Ryanodine receptor 2 (RYR2) mutation accounts for ∼60% of CPVT patients which is inherited in an autosomal dominant pattern. ObjectiveThis study aimed to identify CPVT-related mutations and clinical characteristics among Taiwanese CPVT patients and compare to other cohorts worldwide. MethodsClinical and genetic data were obtained from the Sudden Arrhythmia Death Syndrome Registry in Taiwan (SADS-TW). Forty clinically diagnosed Taiwanese CPVT patients were included. ResultsThis is the first nationwide CPVT cohort in Taiwan. Among the 29 Taiwanese patients with CPVT-related gene mutations, 55% had RYR2 mutations, a rate similar to other ethnicities. Three out of 12 RYR2 variants were unreported. Exercise-induced symptoms including syncope and cardiac arrest were more frequent in East Asian cohorts (Taiwanese 79%, Japanese 91%), compared to Caucasian cohorts (59%) (p = 0.002). ConclusionThe discovery of diverse RYR2 mutations in the Taiwanese CVPT population demonstrates the importance of genetic testing in different ethnicities.

Prevalence of Cerebral Amyloid Angiopathy Pathology and Strictly Lobar Microbleeds in East-Asian Versus Western Populations: A Systematic Review and Meta-Analysis.

Possible differences in the prevalence of cerebral amyloid angiopathy (CAA) in East-Asian compared to Western populations have received little attention, and results so far have been ambiguous. Our aim is to compare the prevalence of CAA neuropathology and magnetic resonance imaging markers of CAA in East-Asian and Western cohorts reflecting the general population, cognitively normal elderly, patients with Alzheimer's disease (AD), and patients with (lobar) intracerebral hemorrhage (ICH). We performed a systematic literature search in PubMed and Embase for original research papers on the prevalence of CAA and imaging markers of CAA published up until February 17th 2022. Records were screened by two independent reviewers. Pooled estimates were determined using random-effects models. We compared studies from Japan, China, Taiwan, South Korea (East-Asian cohorts) to studies from Europe or North America (Western cohorts) by meta-regression models. We identified 12,257 unique records, and we included 143 studies on Western study populations and 53 studies on East-Asian study populations. Prevalence of CAA neuropathology did not differ between East-Asian and Western cohorts in any of the investigated patient domains. The prevalence of strictly lobar microbleeds was lower in East-Asian cohorts of population-based individuals (5.6% vs. 11.4%, P=0.020), cognitively normal elderly (2.6% vs. 11.4%, P=0.001), and patients with ICH (10.2% vs. 24.6%, P<0.0001). However, age was in general lower in the East-Asian cohorts. The prevalence of CAA neuropathology in the general population, cognitively normal elderly, patients with AD, and patients with (lobar) ICH is similar in East-Asian and Western countries. In East-Asian cohorts reflecting the general population, cognitively normal elderly, and patients with ICH, strictly lobar microbleeds were less prevalent, likely due to their younger age. Consideration of potential presence of CAA is warranted in decisions regarding antithrombotic treatment and potential new anti-amyloid-β immunotherapy as treatment for AD in East-Asian and Western countries alike.

Long-term prognosis of acute primary angle closure in an east asian cohort

PurposeTo provide an updated analysis of the long-term outcomes of patients with acute primary angle closure (APAC) and to investigate the risk factors for visual field (VF) loss progression.Study DesignRetrospective, clinical cohort studyMethodsOne hundred and forty-six APAC patients with a minimum of 1-year follow-up were included. The presenting features and the treatment utilized were recorded. The visual and intraocular pressure (IOP) outcomes were analyzed. The main outcome measures were the proportion of blindness and IOP at the final visit. A subset of patients with sufficient VF results was divided into a stable and progressive group based on mean deviation (MD) loss rate. Univariate and multivariate logistic regression analyses were performed to identify predictors of progression.ResultsNine patients (6.2%) were blind, and 76.0% (111/146) had final decimal visual acuity greater than or equal to 0.5. All patients had normal final IOP, and 65.1% (95/146) were medication-free. 64.4% (94/146) underwent cataract surgery at a median 4 months after their APAC attack. The use of topical hypotensive medications (OR = 8.029, P = 0.012) was the only significant predictor of fast MD loss in the multivariate regression.ConclusionsThe long-term outcomes of APAC in recent years have been more promising. All patients maintained normal IOP several years following their APAC attack, and fewer than half required hypotensive agents. The incidence of blindness was low. These findings suggest that current practice patterns in the management of APAC are beneficial.

Association between oral microbiome and five types of respiratory infections: a two-sample Mendelian randomization study in east Asian population.

To explore the causal relationship between the oral microbiome and specific respiratory infections including tonsillitis, chronic sinusitis, bronchiectasis, bronchitis, and pneumonia, assessing the impact of genetic variations associated with the oral microbiome. Mendelian randomization was used to analyze genetic variations, leveraging data from genome-wide association studies in an East Asian cohort to identify connections between specific oral microbiota and respiratory infections. Our analysis revealed that Prevotella, Streptococcus, Fusobacterium, Pauljensenia, and Capnocytophaga play crucial roles in influencing respiratory infections. Prevotella is associated with both promoting bronchitis and inhibiting pneumonia and tonsillitis, with a mixed effect on chronic sinusitis. Streptococcus and Fusobacterium show varied impacts on respiratory diseases, with Fusobacterium promoting chronic sinusitis, bronchiectasis, and bronchitis. Conversely, Pauljensenia and Capnocytophaga are linked to reduced bronchitis and tonsillitis, and inhibited pneumonia and bronchitis, respectively. These findings underscore the significant impact of the oral microbiome on respiratory health, suggesting potential strategies for disease prevention and management through microbiome targeting. The study highlights the complexity of microbial influences on respiratory infections and the importance of further research to elucidate these relationships.

Neuronal intranuclear inclusion disease in New Zealand: A novel discovery

Neuronal intranuclear inclusion disease, caused by a GGC repeat expansion in the 5′-untranslated region of NOTCH2NLC, is a rare neurodegenerative condition with highly variable clinical manifestations. In recent years, the number of reported cases have increased dramatically in East Asia. We report the first four genetically confirmed cases of neuronal intranuclear inclusion disease in New Zealand, all having Polynesian ancestry (three New Zealand Māori and one Cook Island Māori). Phenotypically, they resemble cases reported from recent large East Asian cohorts.

Genetic control of DNA methylation is largely shared across European and East Asian populations

DNA methylation is an ideal trait to study the extent of the shared genetic control across ancestries, effectively providing hundreds of thousands of model molecular traits with large QTL effect sizes. We investigate cis DNAm QTLs in three European (n = 3701) and two East Asian (n = 2099) cohorts to quantify the similarities and differences in the genetic architecture across populations. We observe 80,394 associated mQTLs (62.2% of DNAm probes with significant mQTL) to be significant in both ancestries, while 28,925 mQTLs (22.4%) are identified in only a single ancestry. mQTL effect sizes are highly conserved across populations, with differences in mQTL discovery likely due to differences in allele frequency of associated variants and differing linkage disequilibrium between causal variants and assayed SNPs. This study highlights the overall similarity of genetic control across ancestries and the value of ancestral diversity in increasing the power to detect associations and enhancing fine mapping resolution.

Laparoscopic continuous seromuscular circumsuture for myomectomy: a real-world, retrospective, East-Asian cohort study

ObjectiveThis study aimed to introduce a novel laparoscopic haemostasis for myomectomy and investigate the independent risk factors for uterine fibroid recurrence.DesignA retrospective cohort study.SettingFollowing strengthening the reporting of observational studies...

Abstract TP253: Early Neurological Deterioration Following Small Subcortical Infarcts: A Systematic Review and Meta-Analysis

Background and Objectives: Acute small subcortical infarcts (SSI) result in high rates of early neurological deterioration (END) despite best medical management. Those with SSI-related END have worse functional outcomes after stroke leading to increased morbidity. Presently, it is unknown in a robust manner the incidence or risk factors for END within this demographic. The aim of this study was to perform a systematic review and meta-analysis to understand the incidence and risk factors of SSI-related END. Methods: We searched PubMed, Cochrane Library, and Google Scholar between January 1, 2000, and June 1, 2022, including both retrospective cross-sectional and prospective observational studies. The primary outcome was development of END based on publishing authors’ definition. Abstracted data included age, sex, cohort size, diagnoses of hypertension, hyperlipidemia, diabetes mellitus, study definition of END and SSI, and presence of branch atheromatous disease (BAD) and lesion diameter. Results: We identified 31 studies enrolling 6376 patients. Most studies were conducted in East Asia (27/31, 87%) and had a least some concern for risk of bias. Funnel plot illustrated a high level of publication bias favoring high incidence studies. END was commonly defined as ≥ 2 overall NIHSS change or ≥ 1 motor change within 3 to 7 days from admission (average: 5 days). A pooled proportion of END was 22% (95%CI 0.19 - 0.25, I2 = 91.2%, 31 studies). Meta-regression identified that female sex [risk ratio (RR) 1.23, 95%CI 1.09-1.39, I2=30.8%, 31 studies], diabetes mellitus (RR 1.16 95%CI 1.01-1.33, I2=38.4%, 30 studies), and BAD (RR 1.99 95%CI 1.61-2.46, I2=50.7%, 17 studies) as risk factors for END. Discussion: Our data identified primarily within an East Asian cohort that risk factors for SSI-related END include diabetes mellitus and branch atheromatous disease with a pooled prevalence of END occurring in 1 in 4 patients. Future studies are needed to understand treatment and preventative strategies for this patient population.

Clonal haematopoiesis of indeterminate potential and atrial fibrillation: an east Asian cohort study.

Both clonal haematopoiesis of indeterminate potential (CHIP) and atrial fibrillation (AF) are age-related conditions. This study investigated the potential role of CHIP in the development and progression of AF. Deep-targeted sequencing of 24 CHIP mutations (a mean depth of coverage = 1000×) was performed in 1004 patients with AF and 3341 non-AF healthy subjects. Variant allele fraction ≥ 2.0% indicated the presence of CHIP mutations. The association between CHIP and AF was evaluated by the comparison of (i) the prevalence of CHIP mutations between AF and non-AF subjects and (ii) clinical characteristics discriminated by CHIP mutations within AF patients. Furthermore, the risk of clinical outcomes-the composite of heart failure, ischaemic stroke, or death-according to the presence of CHIP mutations in AF was investigated from the UK Biobank cohort. The mean age was 67.6 ± 6.9 vs. 58.5 ± 6.5 years in AF (paroxysmal, 39.0%; persistent, 61.0%) and non-AF cohorts, respectively. CHIP mutations with a variant allele fraction of ≥2.0% were found in 237 (23.6%) AF patients (DNMT3A, 13.5%; TET2, 6.6%; and ASXL1, 1.5%) and were more prevalent than non-AF subjects [356 (10.7%); P < .001] across the age. After multivariable adjustment (age, sex, smoking, body mass index, diabetes, and hypertension), CHIP mutations were 1.4-fold higher in AF [adjusted odds ratio (OR) 1.38; 95% confidence interval 1.10-1.74, P < .01]. The ORs of CHIP mutations were the highest in the long-standing persistent AF (adjusted OR 1.50; 95% confidence interval 1.14-1.99, P = .004) followed by persistent (adjusted OR 1.44) and paroxysmal (adjusted OR 1.33) AF. In gene-specific analyses, TET2 somatic mutation presented the highest association with AF (adjusted OR 1.65; 95% confidence interval 1.05-2.60, P = .030). AF patients with CHIP mutations were older and had a higher prevalence of diabetes, a longer AF duration, a higher E/E', and a more severely enlarged left atrium than those without CHIP mutations (all P < .05). In UK Biobank analysis of 21 286 AF subjects (1297 with CHIP and 19 989 without CHIP), the CHIP mutation in AF is associated with a 1.32-fold higher risk of a composite clinical event (heart failure, ischaemic stroke, or death). CHIP mutations, primarily DNMT3A or TET2, are more prevalent in patients with AF than non-AF subjects whilst their presence is associated with a more progressive nature of AF and unfavourable clinical outcomes.