An Approach to Identifying Spatial Variability in Observed Infectious Disease Spread in a Prospective Time-Space Series with Applications to COVID-19 and Dengue Incidence.

Most of the growing prospective analytic methods in space-time disease surveillance and intended functions of disease surveillance systems focus on earlier detection of disease outbreaks, disease clusters, or increased incidence. The spread of the virus such as SARS-CoV-2 has not been spatially and temporally uniform in an outbreak. With the identification of an infectious disease outbreak, recognizing and evaluating anomalies (excess and decline) of disease incidence spread at the time of occurrence during the course of an outbreak is a logical next step. We propose and formulate a hypergeometric probability model that investigates anomalies of infectious disease incidence spread at the time of occurrence in the timeline for many geographically described populations (e.g., hospitals, towns, counties) in an ongoing daily monitoring process. It is structured to determine whether the incidence grows or declines more rapidly in a region on the single current day or the most recent few days compared to the occurrence of the incidence during the previous few days relative to elsewhere in the surveillance period. The new method uses a time-varying baseline risk model, accounting for regularly (e.g., daily) updated information on disease incidence at the time of occurrence, and evaluates the probability of the deviation of particular frequencies to be attributed to sampling fluctuations, accounting for the unequal variances of the rates due to different population bases in geographical units. We attempt to present and illustrate a new model to advance the investigation of anomalies of infectious disease incidence spread by analyzing subsamples of spatiotemporal disease surveillance data from Taiwan on dengue and COVID-19 incidence which are mosquito-borne and contagious infectious diseases, respectively. Efficient R programs for computation are available to implement the two approximate formulae of the hypergeometric probability model for large numbers of events.

A Functional Polymorphism Downstream of Vitamin A Regulator Gene CYP26B1 Is Associated with Hand Osteoarthritis.

While genetic analyses have revealed ~100 risk loci associated with osteoarthritis (OA), only eight have been linked to hand OA. Besides, these studies were performed in predominantly European and Caucasian ancestries. Here, we conducted a genome-wide association study in the Han Chinese population to identify genetic variations associated with the disease. We recruited a total of 1136 individuals (n = 420 hand OA-affected; n = 716 unaffected control subjects) of Han Chinese ancestry. We carried out genotyping using Axiom Asia Precisi on Medicine Research Array, and we employed the RegulomeDB database and RoadMap DNase I Hypersensitivity Sites annotations to further narrow down our potential candidate variants. Genetic variants identified were tested in the Geisinger's hand OA cohort selected from the Geisinger MyCode community health initiative (MyCode®). We also performed a luciferase reporter assay to confirm the potential impact of top candidate single-nucleotide polymorphisms (SNPs) on hand OA. We identified six associated SNPs (p-value = 6.76 × 10-7-7.31 × 10-6) clustered at 2p13.2 downstream of the CYP26B1 gene. The strongest association signal identified was rs883313 (p-value = 6.76 × 10-7, odds ratio (OR) = 1.76), followed by rs12713768 (p-value = 1.36 × 10-6, OR = 1.74), near or within the enhancer region closest to the CYP26B1 gene. Our findings showed that the major risk-conferring CC haplotype of SNPs rs12713768 and rs10208040 [strong linkage disequilibrium (LD); D' = 1, r2 = 0.651] drives 18.9% of enhancer expression activity. Our findings highlight that the SNP rs12713768 is associated with susceptibility to and severity of hand OA in the Han Chinese population and that the suggested retinoic acid signaling pathway may play an important role in its pathogenesis.

Levonorgestrel intrauterine devices improve body constitution deviations in the perspective of traditional Chinese medicine and quality of life in patients with chronic pelvic pain and heavy menstrual bleeding.

OBJECTIVE: This study aimed to investigate whether the use of levonorgestrel intrauterine devices (LNG-IUD) in the perspective of traditional Chinese medicine (TCM) can improve the body constitution deviations and quality of life (QoL) in patients with chronic pelvic pain (CPP) and heavy menstrual bleeding (HMB). MATERIALS AND METHODS: To understand the TCM body constitution differences between patients, patients with CPP from a gynecology clinic were first compared to a healthy control group from the Academia Sinica Taiwan Biobank (TWB). Patients with CPP were also compared with patients with pelvic diseases from the TWB. Patients with CPP and HMB, some who under LNG-IUD treatment, underwent tests for physical consistency. After 6-8 months, the TCM body constitution and QoL of patients who received LNG-IUD treatment were reanalyzed. The questionnaires used included the Self-Assessment Chart of Menstrual Bleeding, the Taiwanese version of the Pictorial Blood Loss Assessment Chart, the TCM Body Constitution Questionnaire, the 6-point Behavior Rating Scale, and the Taiwanese version of the Short Form-36 Health Survey. All data were analyzed using Wilcoxon's signed-rank test in SAS 9.4 software. RESULTS: In total, 2932 healthy women and 724 women with pelvic diseases were present in the TWB project. Moreover, 376 patients with CPP were admitted to a gynecology clinic, of whom 42 received LNG-IUD treatment. After LNG-IUD treatment, the primary endpoint was regarded as an improvement in Yang-Xu (lack of energy), Yin-Xu (lack of material), and phlegm stasis (accumulation of pathological products). These findings indicated an improvement in menstrual blood loss, pelvic pain, physical functioning, physical problems, body pain, general health, and emotional problems (p < 0.05). CONCLUSION: LNG-IUD treatment improves body constitution deviations in TCM and QoL in patients with CPP and HMB. Our results provide a valuable reference for the use of modern medicine and TCM in treating CPP and HMB.

Enrichment of Prevotella intermedia in human colorectal cancer and its additive effects with Fusobacterium nucleatum on the malignant transformation of colorectal adenomas.

BACKGROUND: Owing to the heterogeneity of microbiota among individuals and populations, only Fusobacterium nucleatum and Bacteroides fragilis have been reported to be enriched in colorectal cancer (CRC) in multiple studies. Thus, the discovery of additional bacteria contributing to CRC development in various populations can be expected. We aimed to identify bacteria associated with the progression of colorectal adenoma to carcinoma and determine the contribution of these bacteria to malignant transformation in patients of Han Chinese origin. METHODS: Microbiota composition was determined through 16S rRNA V3-V4 amplicon sequencing of autologous adenocarcinomas, adenomatous polyps, and non-neoplastic colon tissue samples (referred to as "tri-part samples") in patients with CRC. Enriched taxa in adenocarcinoma tissues were identified through pairwise comparison. The abundance of candidate bacteria was quantified through genomic quantitative polymerase chain reaction (qPCR) in tissue samples from 116 patients. Associations of candidate bacteria with clinicopathological features and genomic and genetic alterations were evaluated through odds ratio tests. Additionally, the effects of candidate bacteria on CRC cell proliferation, migration, and invasion were evaluated through the co-culture of CRC cells with bacterial cells or with conditioned media from bacteria. RESULTS: Prevotella intermedia was overrepresented in adenocarcinomas compared with paired adenomatous polyps. Furthermore, co-abundance of P. intermedia and F. nucleatum was observed in tumor tissues. More notably, the coexistence of these two bacteria in adenocarcinomas was associated with lymph node involvement and distant metastasis. These two bacteria also exerted additive effects on the enhancement of the migration and invasion abilities of CRC cells. Finally, conditioned media from P. intermedia promoted the migration and invasion of CRC cells. CONCLUSION: This report is the first to demonstrate that P. intermedia is enriched in colorectal adenocarcinoma tissues and enhances the migration and invasion abilities of CRC cells. Moreover, P. intermedia and F. nucleatum exert additive effects on the malignant transformation of colorectal adenomas into carcinomas. These findings can be used to identify patients at a high risk of malignant transformation of colorectal adenomas or metastasis of CRC, and they can accordingly be provided optimal clinical management.

Cardio- and Neurotoxicity of Selected Anti-COVID-19 Drugs.

Since December 2019, the novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected ~435 million people and caused ~6 million related deaths as of March 2022. To combat COVID-19, there have been many attempts to repurpose FDA-approved drugs or revive old drugs. However, many of the current treatment options have been known to cause adverse drug reactions. We employed a population-based drug screening platform using 13 human leukocyte antigen (HLA) homozygous human induced pluripotent cell (iPSC) lines to assess the cardiotoxicity and neurotoxicity of the first line of anti-COVID-19 drugs. We also infected iPSC-derived cells to understand the viral infection of cardiomyocytes and neurons. We found that iPSC-derived cardiomyocytes express the ACE2 receptor which correlated with a higher infection of the SARS-CoV-2 virus (r = 0.86). However, we were unable to detect ACE2 expression in neurons which correlated with a low infection rate. We then assessed the toxicity of anti-COVID-19 drugs and identified two cardiotoxic compounds (remdesivir and arbidol) and four neurotoxic compounds (arbidol, remdesivir, hydroxychloroquine, and chloroquine). These data show that this platform can quickly and easily be employed to further our understanding of cell-specific infection and identify drug toxicity of potential treatment options helping clinicians better decide on treatment options.

Population-based high-throughput toxicity screen of human iPSC-derived cardiomyocytes and neurons.

In this study, we establish a population-based human induced pluripotent stem cell (hiPSC) drug screening platform for toxicity assessment. After recruiting 1,000 healthy donors and screening for high-frequency human leukocyte antigen (HLA) haplotypes, we identify 13 HLA-homozygous "super donors" to represent the population. These "super donors" are also expected to represent at least 477,611,135 of the global population. By differentiating these representative hiPSCs into cardiomyocytes and neurons we show their utility in a high-throughput toxicity screen. To validate hit compounds, we demonstrate dose-dependent toxicity of the hit compounds and assess functional modulation. We also show reproducible in vivo drug toxicity results using mouse models with select hit compounds. This study shows the feasibility of using a population-based hiPSC drug screening platform to assess cytotoxicity, which can be used as an innovative tool to study inter-population differences in drug toxicity and adverse drug reactions in drug discovery applications.

Spatially varying effects of measured confounding variables on disease risk.

BACKGROUND: The presence of considerable spatial variability in incidence intensity suggests that risk factors are unevenly distributed in space and influence the geographical disease incidence distribution and pattern. As most human common diseases that challenge investigators are complex traits and as more factors associated with increased risk are discovered, statistical spatial models are needed that investigate geographical variability in the association between disease incidence and confounding variables and evaluate spatially varying effects on disease risk related to known or suspected risk factors. Information on geography that we focus on is geographical disease clusters of peak incidence and paucity of incidence. METHODS: We proposed and illustrated a statistical spatial model that incorporates information on known or hypothesized risk factors, previously detected geographical disease clusters of peak incidence and paucity of incidence, and their interactions as covariates into the framework of interaction regression models. The spatial scan statistic and the generalized map-based pattern recognition procedure that we recently developed were both considered for geographical disease cluster detection. The Freeman-Tukey transformation was applied to improve normality of distribution and approximately stabilize the variance in the model. We exemplified the proposed method by analyzing data on the spatial occurrence of sudden infant death syndrome (SIDS) with confounding variables of race and gender in North Carolina. RESULTS: The analysis revealed the presence of spatial variability in the association between SIDS incidence and race. We differentiated spatial effects of race on SIDS incidence among previously detected geographical disease clusters of peak incidence and incidence paucity and areas outside the geographical disease clusters, determined by the spatial scan statistic and the generalized map-based pattern recognition procedure. Our analysis showed the absence of spatial association between SIDS incidence and gender. CONCLUSION: The application to the SIDS incidence data demonstrates the ability of our proposed model to estimate spatially varying associations between disease incidence and confounding variables and distinguish spatially related risk factors from spatially constant ones, providing valuable inference for targeted environmental and epidemiological surveillance and management, risk stratification, and thorough etiologic studies of disease.

Genetic factors of idiopathic central precocious puberty and their polygenic risk in early puberty.

OBJECTIVE,: To investigate the genetic characteristics of idiopathic central precocious puberty (ICPP) and validate its polygenic risk for early puberty. DESIGN AND METHODS: A bootstrap subsampling and genome-wide association study were performed on Taiwanese Han Chinese girls comprising 321 ICPP patients and 148 controls. Using previous GWAS data on pubertal timing, a replication study was performed. A validation group was also investigated for the weighted polygenic risk score (wPRS) of the risk of early puberty. RESULTS: A total of 105 SNPs for the risk of ICPP were identified, of which 22 yielded an area under the receiver operating characteristic curve of 0.713 for the risk of early puberty in the validation group. A replication study showed that 33 SNPs from previous GWAS data of pubertal timing were associated with the risk of ICPP (training group: P-value < 0.05). In the validation group, a cumulative effect was observed between the wPRS and the risk of early puberty in a dose-dependent manner (validation group: Cochran-Armitage trend test: P-value < 1.00E-04; wPRS quartile 2 (Q2) (odds ratio (OR) = 5.00, 95% CI: 1.55-16.16), and wPRS Q3 (OR = 11.67, 95% CI: 2.44-55.83)). CONCLUSIONS: This study reveals the ICPP genetic characteristics with 22 independent and 33 reported SNPs in the Han Chinese population from Taiwan. This study may contribute to understand the genetic features and underlying biological pathways that control pubertal timing and pathogenesis of ICPP and also to the identification of individuals with a potential genetic risk of early puberty.

Rare variants discovery by extensive whole-genome sequencing of the Han Chinese population in Taiwan: Applications to cardiovascular medicine.

Introduction: A population-specific genomic reference is important for research and clinical practice, yet it remains unavailable for Han Chinese (HC) in Taiwan. Objectives: We report the first whole genome sequencing (WGS) database of HC (1000 Taiwanese genome (1KTW-WGS)) and demonstrate several applications to cardiovascular medicine. Methods: Whole genomes of 997 HC were sequenced to at least 30X depth. A total of 20,117 relatively healthy HC individuals were genotyped using a customized Axiom GWAS array. We performed a genome-wide genotype imputation technique using IMPUTE2. Results: We identified 26.7 million single-nucleotide variants (SNVs) and 4.2 million insertions-deletions. Of the SNVs, 16.1% were novel relative to dbSNP (build 152), and 34.2% were novel relative to gnomAD. A total of 18,450 healthy HC individuals were genotyped using a customized Genome-Wide Association Study (GWAS) array. We identified hypertension-associated variants and developed a hypertension prediction model based on the correlation between the WGS data and GWAS data (combined clinical and genetic models, AUC 0.887), and also identified 3 novel hyperlipidemia-associated variants. Each individual carried an average of 16.42 (SD = 3.72) disease-causing variants. Additionally, we established an online SCN5A (an important cardiac gene) database that can be used to explore racial differences. Finally, pharmacogenetics studies identified HC population-specific SNVs in genes (CYP2C9 and VKORC1) involved in drug metabolism and blood clotting. Conclusion: This research demonstrates the benefits of constructing a population-specific genomic reference database for precision medicine.

Genetic profiles of 103,106 individuals in the Taiwan Biobank provide insights into the health and history of Han Chinese.

Personalized medical care focuses on prediction of disease risk and response to medications. To build the risk models, access to both large-scale genomic resources and human genetic studies is required. The Taiwan Biobank (TWB) has generated high-coverage, whole-genome sequencing data from 1492 individuals and genome-wide SNP data from 103,106 individuals of Han Chinese ancestry using custom SNP arrays. Principal components analysis of the genotyping data showed that the full range of Han Chinese genetic variation was found in the cohort. The arrays also include thousands of known functional variants, allowing for simultaneous ascertainment of Mendelian disease-causing mutations and variants that affect drug metabolism. We found that 21.2% of the population are mutation carriers of autosomal recessive diseases, 3.1% have mutations in cancer-predisposing genes, and 87.3% carry variants that affect drug response. We highlight how TWB data provide insight into both population history and disease burden, while showing how widespread genetic testing can be used to improve clinical care.

Genome-Wide and Candidate Gene Association Analyses Identify a 14-SNP Combination for Hypertension in Patients With Type 2 Diabetes.

BACKGROUND: High blood pressure is common and comorbid with type 2 diabetes (T2D). Almost 50% of patients with T2D have high blood pressure. Patients with both conditions of hypertension (HTN) and T2D are at risk for cardiovascular diseases and mortality. The study aim was to investigate genetic risk factors for HTN in T2D patients. METHODS: This study included 999 T2D (cohort 1) patients for the first genome scan stage and 922 T2D (cohort 2) patients for the replication stage. Here, we investigated the genetic susceptibility and cumulative weighted genetic risk score for HTN in T2D patients of Han Chinese descent in Taiwan. RESULTS: Thirty novel genetic single nucleotide polymorphisms (SNPs) were associated with HTN in T2D after adjusting for age and body mass index (P value <1 × 10-4). Eight blood pressure-related and/or HTN-related genetic SNPs were associated with HTN in T2D after adjusting for age and body mass index (P value <0.05). Linkage disequilibrium and cumulative weighted genetic risk score analyses showed that 14 of the 38 SNPs were associated with risk of HTN in a dose-dependent manner in T2D (Cochran-Armitage trend test: P value <0.0001). The 14-SNP cumulative weighted genetic risk score was also associated with increased regression tendency of systolic blood pressure in T2D (SBP = 122.05 + 0.8 × weighted genetic risk score; P value = 0.0001). CONCLUSIONS: A cumulative weighted genetic risk score composed of 14 SNPs is important for HTN, increased tendency of systolic blood pressure, and may contribute to HTN risk in T2D in Taiwan.

Association of an IGHV3-66 gene variant with Kawasaki disease.

In a meta-analysis of three GWAS for susceptibility to Kawasaki disease (KD) conducted in Japan, Korea, and Taiwan and follow-up studies with a total of 11,265 subjects (3428 cases and 7837 controls), a significantly associated SNV in the immunoglobulin heavy variable gene (IGHV) cluster in 14q33.32 was identified (rs4774175; OR = 1.20, P = 6.0 × 10-9). Investigation of nonsynonymous SNVs of the IGHV cluster in 9335 Japanese subjects identified the C allele of rs6423677, located in IGHV3-66, as the most significant reproducible association (OR = 1.25, P = 6.8 × 10-10 in 3603 cases and 5731 controls). We observed highly skewed allelic usage of IGHV3-66, wherein the rs6423677 A allele was nearly abolished in the transcripts in peripheral blood mononuclear cells of both KD patients and healthy adults. Association of the high-expression allele with KD strongly indicates some active roles of B-cells or endogenous immunoglobulins in the disease pathogenesis. Considering that significant association of SNVs in the IGHV region with disease susceptibility was previously known only for rheumatic heart disease (RHD), a complication of acute rheumatic fever (ARF), these observations suggest that common B-cell related mechanisms may mediate the symptomology of KD and ARF as well as RHD.

Detecting Genetic Ancestry and Adaptation in the Taiwanese Han People.

The Taiwanese people are composed of diverse indigenous populations and the Taiwanese Han. About 95% of the Taiwanese identify themselves as Taiwanese Han, but this may not be a homogeneous population because they migrated to the island from various regions of continental East Asia over a period of 400 years. Little is known about the underlying patterns of genetic ancestry, population admixture, and evolutionary adaptation in the Taiwanese Han people. Here, we analyzed the whole-genome single-nucleotide polymorphism genotyping data from 14,401 individuals of Taiwanese Han collected by the Taiwan Biobank and the whole-genome sequencing data for a subset of 772 people. We detected four major genetic ancestries with distinct geographic distributions (i.e., Northern, Southeastern, Japonic, and Island Southeast Asian ancestries) and signatures of population mixture contributing to the genomes of Taiwanese Han. We further scanned for signatures of positive natural selection that caused unusually long-range haplotypes and elevations of hitchhiked variants. As a result, we identified 16 candidate loci in which selection signals can be unambiguously localized at five single genes: CTNNA2, LRP1B, CSNK1G3, ASTN2, and NEO1. Statistical associations were examined in 16 metabolic-related traits to further elucidate the functional effects of each candidate gene. All five genes appear to have pleiotropic connections to various types of disease susceptibility and significant associations with at least one metabolic-related trait. Together, our results provide critical insights for understanding the evolutionary history and adaption of the Taiwanese Han population.

Genetic risk score constructed from common genetic variants is associated with cardiovascular disease risk in type 2 diabetes mellitus.

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) experience a two-fold increased risk of cardiovascular diseases. Genome-wide association studies (GWAS) have identified T2DM susceptibility genetic variants. Interestingly, the genetic variants associated with cardiovascular disease risk in T2DM Han Chinese remain to be elucidated. The present study aimed to investigate the genetic variants associated with cardiovascular disease risk in T2DM. METHODS: We performed bootstrapping, GWAS and an investigation of genetic variants associated with cardiovascular disease risk in a discovery T2DM cohort and in a replication cohort. The discovery cohort included 326 cardiovascular disease patients and 1209 noncardiovascular disease patients. The replication cohort included 68 cardiovascular disease patients and 317 noncardiovascular disease patients. The main outcome measures were genetic variants for genetic risk score (GRS) in cardiovascular disease risk in T2DM. RESULTS: In total, 35 genetic variants were associated with cardiovascular disease risk. A GRS was generated by combining risk alleles from these variants weighted by their estimated effect sizes (log odds ratio [OR]). T2DM patients with weighted GRS ≥ 12.63 had an approximately 15-fold increase in cardiovascular disease risk (odds ratio = 15.67, 95% confidence interval [CI] = 10.33-24.00) compared to patients with weighted GRS < 10.39. With the addition of weighted GRS, receiver-operating characteristic curves showed that area under the curve with conventional risk factors was improved from 0.719 (95% CI = 0.689-0.750) to 0.888 (95% CI = 0.866-0.910). CONCLUSIONS: These 35 genetic variants are associated with cardiovascular disease risk in T2DM, alone and cumulatively. T2DM patients with higher levels of weighted genetic risk score have higher cardiovascular disease risks.

Identification of type 2 diabetes loci in 433,540 East Asian individuals.

Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D)1,2; however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells3. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes-NKX6-3 and ANK1-in different tissues4-6. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways.

Glucose transporter 10 modulates adipogenesis via an ascorbic acid-mediated pathway to protect mice against diet-induced metabolic dysregulation.

The development of type 2 diabetes mellitus (T2DM) depends on interactions between genetic and environmental factors, and a better understanding of gene-diet interactions in T2DM will be useful for disease prediction and prevention. Ascorbic acid has been proposed to reduce the risk of T2DM. However, the links between ascorbic acid and metabolic consequences are not fully understood. Here, we report that glucose transporter 10 (GLUT10) maintains intracellular levels of ascorbic acid to promote adipogenesis, white adipose tissue (WAT) development and protect mice from high-fat diet (HFD)-induced metabolic dysregulation. We found genetic polymorphisms in SLC2A10 locus are suggestively associated with a T2DM intermediate phenotype in non-diabetic Han Taiwanese. Additionally, mice carrying an orthologous human Glut10G128E variant (Glut10G128E mice) with compromised GLUT10 function have reduced adipogenesis, reduced WAT development and increased susceptibility to HFD-induced metabolic dysregulation. We further demonstrate that GLUT10 is highly expressed in preadipocytes, where it regulates intracellular ascorbic acid levels and adipogenesis. In this context, GLUT10 increases ascorbic acid-dependent DNA demethylation and the expression of key adipogenic genes, Cebpa and Pparg. Together, our data show GLUT10 regulates adipogenesis via ascorbic acid-dependent DNA demethylation to benefit proper WAT development and protect mice against HFD-induced metabolic dysregulation. Our findings suggest that SLC2A10 may be an important HFD-associated susceptibility locus for T2DM.

Genetic Architecture Associated With Familial Short Stature.

CONTEXT: Human height is an inheritable, polygenic trait under complex and multilocus genetic regulation. Familial short stature (FSS; also called genetic short stature) is the most common type of short stature and is insufficiently known. OBJECTIVE: To investigate the FSS genetic profile and develop a polygenic risk predisposition score for FSS risk prediction. DESIGN AND SETTING: The FSS participant group of Han Chinese ancestry was diagnosed by pediatric endocrinologists in Taiwan. PATIENTS AND INTERVENTIONS: The genetic profiles of 1163 participants with FSS were identified by using a bootstrapping subsampling and genome-wide association studies (GWAS) method. MAIN OUTCOME MEASURES: Genetic profile, polygenic risk predisposition score for risk prediction. RESULTS: Ten novel genetic single nucleotide polymorphisms (SNPs) and 9 reported GWAS human height-related SNPs were identified for FSS risk. These 10 novel SNPs served as a polygenic risk predisposition score for FSS risk prediction (area under the curve: 0.940 in the testing group). This FSS polygenic risk predisposition score was also associated with the height reduction regression tendency in the general population. CONCLUSION: A polygenic risk predisposition score composed of 10 genetic SNPs is useful for FSS risk prediction and the height reduction tendency. Thus, it might contribute to FSS risk in the Han Chinese population from Taiwan.

Targeted Next Generation Sequencing for Genetic Mutations of Dilated Cardiomyopathy.

BACKGROUND: Approximately one-third of cases of dilated cardiomyopathy (DCM) are caused by genetic mutations. With new sequencing technologies, numerous variants have been associated with this inherited cardiomyopathy, however the prevalence and genotype-phenotype correlations in different ethnic cohorts remain unclear. This study aimed to investigate the variants in Chinese DCM patients and correlate them with clinical presentations and prognosis. METHODS AND RESULTS: From September 2013 to December 2016, 70 index patients underwent DNA sequencing for 12 common disease-causing genes with next generation sequencing. Using a bioinformatics filtering process, 12 rare truncating variants (7 nonsense variants, 4 frameshift variants, and 1 splice site variant) and 29 rare missense variants were identified. Of these, 3 patients were double heterozygotes and 10 patients were compound heterozygotes. Overall, 47.1% (33/70) of the index patients had the seputatively pathogenic variants. The majority (33/41, 80.4%) of these variants were located in titin (TTN). More than 80% of the TTN variants (27/33, 81.8%) were distributed in the A band region of the sarcomere. Patients carrying these variants did not have a different phenotype in disease severity, clinical outcome and reversibility of ventricular function compared with non-carriers. CONCLUSIONS: Several new rare variants were identified in a Chinese population in this study, indicating that there are ethnic differences in genetic mutations in DCM patients. TTN remains the major disease-causing gene. Our results could be a reference for future genetic tests in Chinese populations. No specific genotype-phenotype correlations were found, however a prospective large cohort study may be needed to confirm our findings.

Genome-wide association study of morbid obesity in Han Chinese.

BACKGROUND: As obesity is becoming pandemic, morbid obesity (MO), an extreme type of obesity, is an emerging issue worldwide. It is imperative to understand the factors responsible for huge weight gain in certain populations in the modern society. Very few genome-wide association studies (GWAS) have been conducted on MO patients. This study is the first MO-GWAS study in the Han-Chinese population in Asia. METHODS: We conducted a two-stage GWAS with 1110 MO bariatric patients (body mass index [BMI] ≥ 35 kg/m2) from Min-Sheng General Hospital, Taiwan. The first stage involved 575 patients, and 1729 sex- and age-matched controls from the Taiwan Han Chinese Cell and Genome Bank. In the second stage, another 535 patients from the same hospital were genotyped for 52 single nucleotide polymorphisms (SNPs) discovered in the first stage, and 9145 matched controls from Taiwan Biobank were matched for confirmation analysis. RESULTS: The results of the joint analysis for the second stage revealed six top ranking SNPs, including rs8050136 (p-value = 7.80 × 10- 10), rs9939609 (p-value = 1.32 × 10- 9), rs1421085 (p-value = 1.54 × 10- 8), rs9941349 (p-value = 9.05 × 10- 8), rs1121980 (p-value = 7.27 × 10- 7), and rs9937354 (p-value = 6.65 × 10- 7), which were all located in FTO gene. Significant associations were also observed between MO and RBFOX1, RP11-638 L3.1, TMTC1, CBLN4, CSMD3, and ERBB4, respectively, using the Bonferroni correction criteria for 52 SNPs (p < 9.6 × 10- 4). CONCLUSION: The most significantly associated locus of MO in the Han-Chinese population was the well-known FTO gene. These SNPs located in intron 1, may include the leptin receptor modulator. Other significant loci, showing weak associations with MO, also suggested the potential mechanism underlying the disorders with eating behaviors or brain/neural development.