Asian Ancestry Research Articles

Estimating the impact of transmitted and non-transmitted psychiatric and neurodevelopmental polygenic scores on youth emotional problems

Anxiety and depression (emotional disorders) are familial and heritable, especially when onset is early. However, other cross-generational studies suggest transmission of youth emotional problems is explained by mainly environmental risks. We set out to test the contribution of parental non-transmitted genetic liability, as indexed by psychiatric/neurodevelopmental common polygenic liability, to youth emotional problems using a UK population-based cohort: the Millennium Cohort Study. European (N = 6328) and South Asian (N = 814) ancestries were included, as well as a subset with genomic data from both parents (European: N = 2809; South Asian: N = 254). We examined the association of transmitted (PGST) and non-transmitted polygenic scores (PGSNT) for anxiety, depression, bipolar disorder and neurodevelopmental disorders (attention-deficit/hyperactivity disorder [ADHD], autism spectrum disorder [ASD], schizophrenia) with youth emotional disorder and symptom scores, measured using the parent- and self-reported Strengths and Difficulties Questionnaire emotional subscale at 6 timepoints between ages 3–17 years. In the European sample, PGST for anxiety and depression, but not bipolar disorder, were associated with emotional disorder and symptom scores across all ages, except age 3, with strongest association in adolescence. ADHD and ASD PGST also showed association across ages 11–17 years. In the South Asian sample, evidence for associations between all PGST and outcome measures were weaker. There was weak evidence of association between PGSNT for anxiety and depression and age 17 symptom scores in the South Asian sample, but not in the European sample for any outcome. Overall, PGST for depression, anxiety, ADHD and ASD contributed to youth emotional problems, with stronger associations in adolescence. There was limited support for non-transmitted genetic effects: these findings do not support the hypothesis that parental polygenic psychiatric/neurodevelopmental liability confer risk to offspring emotional problems through non-transmitted rearing/nurture effects.

CYP2C19 genotype prevalence and association with recurrent myocardial infarction in British-South Asians treated with clopidogrel

Abstract Background Pharmacogenomics examines how genes and drugs interact to explain some of the inter-individual variability in response to medications. CYP2C19 is a hepatic enzyme involved in the metabolism of clopidogrel from a prodrug to its active metabolite. Although the European Society of Cardiology and National Institute for Care Excellence recommend ticagrelor (a non CYP2C19 dependent P2Y12 antagonist) as the antiplatelet agent of choice, clopidogrel remains widely prescribed for acute coronary syndrome and myocardial infarction. CYP2C19 poor metabolizers are known to be more common in Asian ancestry but very few studies have looked specifically at South Asian populations or linked metabolizer diplotypes with clinical efficacy data in this population. The outcome studies on which clopidogrel was licensed for efficacy and safety did not include significant South Asian representation. Furthermore, South Asians are known to have a higher prevalence of cardio-metabolic disease compared with European ancestry populations. Methods We studied the Genes & Health cohort of British Bangladeshi and Pakistani ancestry participants to look at prevalence of CYP2C19 metabolizer genotypes and correlate these with recurrent myocardial infarction risk for those who had been prescribed clopidogrel in primary care. Multivariable regression was used to test for association between known CYP2C19 diptotypes and recurrent myocardial infarction in those prescribed clopidogrel, controlling for known CVD risk factors, percutaneous coronary intervention, age, and gender. Results Genes & Health cohort participants (N = 44,396) have a high prevalence (57%) of intermediate or poor CYP2C19 metabolizers, with at least 1 loss of function allele. The prevalence of poor metabolizers carrying 2 CYP2C19 loss of function alleles is 13%, which is higher than in previously studied European (2.4%) and Central/South Asian populations (8.2%). This is primarily due to the *2 LOF allele present in 56% of the population. 69% of the cohort who were diagnosed with an acute MI were prescribed clopidogrel. The presence of the poor metabolizer diplotype is significantly associated with higher risk of recurrent MI, or failed secondary prevention on clopidogrel in this population, OR 3.1 (p = 0.02), with some subsequent ischemic events already described in this young cohort (Acute MI prescribed clopidogrel N = 697, Recurrent MI in this group N=39). Conclusions A pharmacogenomic-driven approach to clopidogrel prescribing has the potential to impact significantly on clinical management and outcomes in individuals of Bangladeshi and Pakistani ancestry. In absence of genotype guided prescribing, maximal adherence to guidelines recommending non CYP2C19 dependent P2Y12 anti-platelet therapy is likely to be disproportionately beneficial in this ethnic cohort.Risk of recurrent MICentral illustration

Comparing the drug target effects of Cholesteryl ester transfer protein (CETP) on cardiovascular diseases in East Asian and European populations

Abstract Introduction Cholesteryl ester transfer protein (CETP) is a drug target originally evaluated for raising HDL-C, for efficacy against coronary heart disease (CHD). Previous attempts to develop a licensed drug compound inhibiting CETP have heterogeneous CHD effects, which are likely attributable to the developed compound rather than CETP itself. Currently, novel CETP inhibitors are being pursued for the treatment of CHD. Drug target Mendelian randomization studies, leveraging genetic evidence, have shown that on-target CETP inhibition reduces CHD risk in individuals of European ancestries. However, similar MR studies conducted in East Asian ancestries have failed to show a CHD effect, questioning the value of pharmacological inhibition of CETP in this population. Purpose In this study, we compared drug target MR effects of CETP inhibition in Europeans and East Asians, focusing on cardiovascular efficacy outcomes, and relevant safety outcomes. Methods We used ancestry-specific GWAS summary statistics for Europeans (n=1,320,016) and East Asians (n=146,492) from the Global Lipids Genetics Consortium, taking variants from within and around ±50 kbp of the CETP locus. Colocalization was employed to determine potential trans-ancestry signals between CETP variants for HDL-C and LDL-C. Subsequently, drug target MR was used to estimate ancestry-specific effects of on-target CETP inhibition on 11 plasma biomarkers and 15 clinical outcomes between East Asian and European populations. Differences between ancestries were evaluated using interaction tests. Results There was strong support (posterior probability: 99.8%) of a shared causal CETP variant affecting HDL-C in both populations. Given the absence of a LDL-C signal in East Asians, similar colocalization was not observed for LDL-C. Employing drug target MR scaled to a standard deviation increase in HDL-C, we found that lower CETP had more pronounced decreasing effects in Europeans on LDL-C, LP[a], systolic blood pressure and pulse pressure (interaction p-values >1.9×10-3). Nevertheless, lower CETP protected against CHD, angina, intracerebral haemorrhage, and heart failure in both ancestries, for example for CHD (OR, 0.89; 95%CI, 0.84-0.94) in East Asians, compared to Europeans (OR, 0.95; 95%CI, 0.92-0.99, interaction p-value: 0.05). Exploring potential safety outcomes, lower CETP was protective against pneumonia in Europeans and East Asians (interaction p-value=0.53) and had a potential harmful effect on asthma and chronic kidney disease in East Asians (interaction p-value > 1.9×10-3). Conclusion In conclusion, on-target and sufficiently potent CETP inhibition is anticipated to prevent cardiovascular diseases in both European and East Asian populations.

Abstract 14019: Comparing the Effect Profile of CETP in Individuals of East Asian and European Ancestries

Introduction: Cholesteryl ester transfer protein (CETP) is a lipid drug target under development for CHD in both European and East Asian populations.Previous drug target Mendelian randomization (MR) studies conducted in East Asians failed to show a CHD effect, which has been interpreted as lack of effectiveness of CETP inhibition for CHD prevention in this population. Hypothesis: In this study, we inferred the effect of CETP inhibition in individuals of European and East Asian ancestries using drug target Mendelian randomization. Methods: We leveraged genetic associations of CETP variants with major blood lipid fractions for individuals of European (n=1,320,016) and East Asian (n=146,492) ancestries. Colocalization was employed to identify potential cross-ancestry signals of CETP variants for plasma concentrations of LDL-C or HDL-C. Drug target MR was used to estimate ancestry-specific effects of on-target CETP inhibition. Differences between ancestries were evaluated using interaction tests, applying a multiplicity corrected alpha of 1.9х10 -3 based on the 26 considered traits. Results: There was strong support (posterior probability=1.00) of a shared causal CETP variant affecting HDL-C in both populations, which was not observed for LDL-C. Employing drug target MR scaled to a standard deviation increase in HDL-C, we found that lower CETP was associated with lower LDL-C, Lp[a], systolic blood pressure and pulse pressure in both groups, but the effects were more pronounced in European individuals (interaction p-values < 1.9х10-3). Lower CETP was protective against CHD, angina, intracerebral haemorrhage and heart failure in both ancestries, for example for CHD in East Asians (OR 0.89, 95%CI 0.84;0.94) compared to Europeans (OR 0.95, 95%CI 0.92;0.99, interaction p-value=0.05). Conclusions: In conclusion, on-target inhibition of CETP is anticipated to decrease cardiovascular disease in individuals of both European and East Asian ancestries.

Abstract 12687: Evaluating a Coronary Artery Disease Polygenic Risk Score Screening Strategy in a Diverse Patient Cohort at UCLA

Introduction: Recent efforts to predict and mitigate coronary artery disease (CAD) risk have incorporated polygenic risk scores (PGS). Few studies examine the clinical impact of these PGS screening strategies or quantify their performance in clinical terms. Here we estimate the number needed to screen (NNS) of a PGS screening strategy for CAD based using a diverse electronic health record (EHR) linked biobank at UCLA Health. Methods: We leveraged longitudinal EHR data to conduct a synthetic trial. We assumed PGS screening was performed on 6/1/2013 for patients established prior to 1/1/2013 or 6 months into follow time if established later. Patients with preexisting cardiovascular disease or strong statin indications (LDL > 190, diabetes or already on statins) are excluded. Patients with PGS scores in the top 5% of their genetic ancestry groupings (European, East Asian, African, Hispanic) are assumed to have been started on statins for the median 6.9 years of follow up. CAD diagnosis during follow up time was determined by ICD codes. NNS to prevent one CV event is calculated from cohort size and events assuming a statin number needed to treat of 50. Results: Of 33,789 adults, 17,074 were low risk and eligible for PGS screening (35% male with a mean age of 44). NNS to detect one CAD diagnosis was 351, 359, 814, 159 in the European, Hispanic, East Asian and African ancestry groups and NNS to prevent one cardiovascular event was 17,550, 17,950, 40,700, 7,950 respectively. Conclusion: Although PGS accuracy is lower in African ancestry individuals as compared to Europeans, the clinical utility of this PGS-based screening is highest in African ancestries due to increased baseline rates of disease in the African genetic ancestry grouping. Our results demonstrate that PGS accuracy is distinct from clinical utility of PGS-based strategies. Evaluation of screening strategies rather than accuracy alone will be required before PGS screening implementation.

Abstract 18411: The Causal Association Between Coronary Artery Disease and Atrial Fibrillation in East Asian Ancestry

Background: Previous studies have reported a causal association between coronary artery disease (CAD) and atrial fibrillation (AF) in the European populations. However, it is unclear whether the causal association the exists in East Asian populations. Methods: We assessed the causal relationship between CAD and AF using 2-sample Mendelian randomization (MR) in the East Asian populations. Additionally, we performed multivariable MR, correcting obesity, smoking initiation, alcohol intake frequency, and hypertension to further explore the causality between CAD and AF. Results: The calculated odds ratios (ORs) and 95% confidence intervals (CIs) for CAD using inverse-variance weighted, MR-Egger, and weighted-median analysis were 0.984 (0.955-1.014; P = 0.285), 0.957 (0.899-1.019; P = 0.191), and 0.974 (0.945-1.004; P = 0.088), respectively; for AF, the results were 1.066 (0.944-1.203; P = 0.302), 0.790 (0.546-1.142; P = 0.216), and 1.258 (1.098-1.441; P < 0.001). After adjusting common risk factors, the genetically predicted CAD was also causally associated with an 18.5% increased risk of AF (OR = 1.185; 95% CI = 1.065-1.319; P = 0.002), but no causal effect of AF on the risk of CAD. Conclusions: Our findings suggest that genetically predicted CAD is causally associated with an increased risk of AF in East Asian populations.

Abstract 12995: South Asian Representation in Cardiovascular Disease Randomized Controlled Trials

Introduction: South Asian individuals are at higher risk for atherosclerotic cardiovascular disease (ASCVD) compared to individuals of European descent. Although US practice guidelines uniquely recognize South Asian ancestry as a risk-enhancing factor for ASCVD, the degree to which South Asian individuals are included in clinical trials is unknown. We sought to evaluate South Asian representation in major cardiovascular disease (CVD) randomized controlled trials (RCTs) reported in major medical journals. Hypothesis: South Asian individuals are under-represented relative to the global South Asian population in CVD RCTs. Methods: We extracted citations of CVD RCTs reported from 2018 to 2022. Studies were identified as RCTs based on reported randomization of participants and the publication of post-randomization data. We determined self-reported representation rates for South Asian individuals across all studies and further stratified representation rates by clinical trial phase, type of intervention under investigation, and country of origin. Post-randomization participant representation rates were estimated for South Asian individuals and compared to other self-reported racial/ethnic groups. Results: 588,329 participants were enrolled across 128 included trials. Conditions studied included CVA (17.97%), HF (12.50%), CAD (11.72%), HTN (7.81%), ASCVD screening/prevention (7.81%), and others. 2,753 of all CVD RCT participants were South Asian individuals, corresponding to a representation rate of 0.47%. No South Asian individuals had available post-randomization data, whereas post-randomization data were reported for 164,035 white individuals, 20,459 Black individuals, and 6,040 Hispanic individuals. Conclusions: Although South Asian individuals comprise nearly a quarter of the global population and have well-documented excess CVD risk, they represent a small minority of CVD trial participants. No RCTs reported South Asian participant-level data, which limits the generalizability of study findings to South Asians.

Evaluation of optimal methods and ancestries for calculating polygenic risk scores in East Asian population

Polygenic risk scores (PRSs) have been studied for predicting human diseases, and various methods for PRS calculation have been developed. Most PRS studies to date have focused on European ancestry, and the performance of PRS has not been sufficiently assessed in East Asia. Herein, we evaluated the predictive performance of PRSs for East Asian populations under various conditions. Simulation studies using data from the Korean cohort, Health Examinees (HEXA), demonstrated that SBayesRC and PRS-CS outperformed other PRS methods (lassosum, LDpred-funct, and PRSice) in high fixed heritability (0.3 and 0.7). In addition, we generated PRSs using real-world data from HEXA for ten diseases: asthma, breast cancer, cataract, coronary artery disease, gastric cancer, glaucoma, hyperthyroidism, hypothyroidism, osteoporosis, and type 2 diabetes (T2D). We utilized the five previous PRS methods and genome-wide association study (GWAS) data from two biobank-scale datasets [European (UK Biobank) and East Asian (BioBank Japan) ancestry]. Additionally, we employed PRS-CSx, a PRS method that combines GWAS data from both ancestries, to generate a total of 110 PRS for ten diseases. Similar to the simulation results, SBayesRC showed better predictive performance for disease risk than the other methods. Furthermore, the East Asian GWAS data outperformed those from European ancestry for breast cancer, cataract, gastric cancer, and T2D, but neither of the two GWAS ancestries showed a significant advantage on PRS performance for the remaining six diseases. Based on simulation data and real data studies, it is expected that SBayesRC will offer superior performance for East Asian populations, and PRS generated using GWAS from non-East Asian may also yield good results.

Ecological Constraints and Drivers for Human Dispersals and Adaptations in the Late Pleistocene and Early Holocene Environments of the East Siberian Arctic

Starting roughly 50,000 years ago, the Arctic region of East Siberia remained continuously populated by groups of anatomically modern humans including the most uncomfortable episodes in the development of the late Quaternary environment; for some of them, human presence in the area became ephemeral. At present, archaeological fossil records allow for distinguishing three main stages in human occupation of the area: Early (~50 to ~29 ka, MIS 3), middle (~29 to ~11.7 ka, MIS 2), and late (from 11.7 to ~8 ka). For most of the time, they the populated open landscapes of the Mammoth Steppe, which declined at the onset of the Holocene. Human settlement of the Arctic was driven by various abiotic and biotic factors and thus archaeologically visible cardinal cultural and technological changes correspond to the most important paleoclimatic and habitat changes in the late Pleistocene and early Holocene. Successful peopling of the Arctic was largely facilitated by the adoption of critically important innovations such as sewing technology based on the use of the eyed bone needle and the manufacture of long shafts and pointed implements made of mammoth tusks. Mammoth exploitation is seen in mass accumulations of mammoths formed by hunting. An obvious connection between archaeological materials and such accumulations is observed in the archaeological record. In the lithic technology, the early stage is presented by archaic-looking flake industries. Starting the LGM, the wedge-core based-microblade technology known as the Beringian microblade tradition spread widely following the shrinkage of the mammoth range. At the late stage, starting at the Holocene boundary, microprismatic blade technology occurs. In all stages, the complex social behavior of the ancient Arctic settlers is revealed. The long-distance transport of products, knowledge, and genes occurs due to the introduction of the land transportation system. Initial human settlement of this region is associated with carriers of the West Eurasian genome who became replaced by the population with East Asian ancestry constantly moving North under the pressure of climate change.

Deconstructing the genetic architecture of treatment-resistant schizophrenia in East Asian ancestry

BackgroundTreatment-resistant schizophrenia (TRS) affects a substantial proportion of patients who do not respond adequately to antipsychotic medications, yet the underlying biological mechanism remains poorly understood. This study investigates the link between the genetic predisposition to schizophrenia and TRS. Methods857 individuals diagnosed with schizophrenia were divided into TRS (n = 142) and non-TRS (n = 715) based on well-defined TRS criteria. Polygenic risk scores (PRS) were calculated using schizophrenia genome-wide association summary statistics from East-Asian and European ancestry populations. PRS was estimated using both P-value thresholding and Bayesian framework methods. Logistic regression analyses were performed to differentiate between TRS and non-TRS individuals. ResultsThe schizophrenia PRS derived from the East-Asian training dataset effectively distinguished between TRS and non-TRS individuals (R2 = 0.029, p = 4.86 ×10-5, pT = 0.1, OR = 1.52, 95% CI = 1.242–1.861), with higher PRS values observed in the TRS group. Similar PRS analysis was conducted based on the European ancestry GWAS summary statistics, but we found superior prediction based on the East-Asian ancestry discovery data. ConclusionThis study reveals an association between common risk variants for schizophrenia and TRS status, suggesting that the genetic burden of schizophrenia may partly contribute to treatment resistance in individuals with schizophrenia. These findings propose the potential use of genetic risk factors for early TRS identification and timely access to clozapine. However, the ancestral background of the discovery sample is crucial for successfully implementing PRS in clinical settings.

British South Asian ancestry participants views of pharmacogenomics clinical implementation and research: a thematic analysis

BackgroundSouth Asian ancestry populations are underrepresented in genomic studies and therapeutics trials. British South Asians suffer from multi-morbidity leading to polypharmacy. Our objective was to elucidate British South Asian ancestry community perspectives on pharmacogenomic implementation and sharing pharmacogenomic clinical data for research.MethodsFour focus groups were conducted (9–12 participants in each). Two groups were mixed gender, while one group was male only and one was female only. Simultaneous interpretation was available to participants in Urdu and Bengali. Focus groups were recorded and abridged transcription and thematic analysis were undertaken.ResultsThere were 42 participants, 64% female. 26% were born in the UK or Europe. 52% were born in Bangladesh and 17% in Pakistan. 36% reported university level education.Implementation of pharmacogenomics was perceived to be beneficial to individuals but pose a risk of overburdening resource limited systems. Pharmacogenomic research was perceived to be beneficial to the community, with concerns about data privacy and misuse. Data sharing was desirable if the researchers did not have a financial stake, and benefits would be shared.Trust was the key condition for the acceptability of both clinical implementation and research. Trust was linked with medication compliance. Education, outreach, and communication facilitate trust.Conclusions (Significance and Impact of the Study)Pharmacogenomics implementation with appropriate education and communication has the potential to enhance trust and contribute to increased medication compliance. Trust drives data sharing, which would enable enhanced representation in research. Representation in scientific evidence base could cyclically enhance trust and compliance.

Systemic lupus erythematosus is associated with lower risk of hepatitis B virus infection: A multivariable Mendelian randomization study in East Asian population.

The relationship between systemic lupus erythematosus (SLE) and hepatitis B virus (HBV) infection is still unclear.We conducted a two-sample Mendelian randomization (MR) analysis using summary statistics from genome-wide association studiesfor SLE and HBV infection in individuals of East Asian ancestry. The inverse-variance weighted (IVW) method, weighted median (WM) method, and MR-Egger method were used to estimate the causal effect of SLE on HBV infection. Additionally, we performed a multivariable MRanalysis adjusting for the effects of body mass indexand rheumatoid arthritis.This MRstudy included a total of 225 106 individuals of East Asian ancestry, comprising 5616 cases and 219 490 controls. The IVW method (OR: 0.79, p = 3.34E-08) and the WM method (OR: 0.79, p = 9.09E-06) revealed a causal relationship between genetically predicted SLE and a low risk of HBV infection. The multivariable MRanalysis still suggested a low risk of HBV infection associated with SLE (OR: 0.83, p = 2.89E-06).Our MRanalysis supports a causal relationship between SLE and a low risk of HBV infection in individuals of East Asian ancestry.

Atopic Dermatitis in Individuals of Asian and African Ancestry: A Scoping Systematic Review

Introduction: Atopic Dermatitis (AD) affects individuals from all ethnicities and backgrounds. It has the highest global disease burden of dermatoses. There is a widely held belief that the presentation of AD is not described well in individuals with non-European ancestry in peer-reviewed literature. However, to our knowledge, this has not been investigated previously Objective: To quantify the number of peer-reviewed literature describing the appearance of clinical features of AD in non-European ancestry, particularly those originating from the Asian and African continents. Methods: A systematic scoping review between December 2020 and January 2021 was performed to quantify the number of studies describing AD in individuals of African and Asian ancestry. Reuslts: Sixteen studies were identified. None of the studies provided a clear description of AD in our population groups. Two studies described features of lichen planus like-AD in African American individuals. All studies reported on observed clinical features of AD. Conclusions: The review confirmed a lack of literature describing AD in populations of non-European heritage. It should encourage authors to make a deliberate effort to describe the appearance of clinical features of AD to enable understanding of how they may differentiate in individuals originating from different parts of the globe.

Worldwide Incidence of Ocular Melanoma and Correlation With Pigmentation-Related Risk Factors.

The worldwide incidence of ocular melanoma (OM), uveal melanoma (UM), and conjunctival melanoma has last been reported on 15years ago. Recently, light iris color and four specific single-nucleotide-polymorphisms (SNPs) have been identified as a UM-risk factor. Furthermore, six iris color predicting SNPs have been discovered (IrisPlex). Interestingly, two of these (rs129138329 and rs12203592) are also UM-risk factors. We collected worldwide incidence data of OM and investigated its correlations with iris color, IrisPlex SNPs, and UM-risk SNPs. Cases of OM, as defined by the International Classification of Diseases Oncology C69 (eye), 8720/3 to 8790/3 (malignant melanoma), and 8000 to 8005 (malignant neoplasm), between 1988 and 2012, were extracted from the Cancer Incidence in Five Continents. Incidence rates were age-standardized and their trends were analyzed with joinpoint regression and age period cohort modeling. Frequencies for each country of iris color, IrisPlex SNPs, and UM-risk SNPs were collected from the literature. Incidence rates were generally ≥8.0 cases per million person-years in Northern Europe, Western Europe, and Oceania; 2.0 to 7.9 in North America, Eastern Europe, and Southern Europe; and <2.0 in South America, Asia, and Africa. OM incidence correlated with latitude (r = 0.77, P ≤ 0.001) and is expressed as a north-to-south decreasing gradient in Europe. SNP rs12913832 correlated with OM incidence (r = 0.83, P ≤ 0.001), blue iris color (r = 0.56, P ≤ 0.05), green iris color (r = 0.51, P ≤ 0.05), and brown iris color (r = -0.64, P ≤ 0.01). Trends were stable for most countries (28/35). OM incidence is highest in populations of European ancestry and lowest in populations of Asian and African ancestry. Overall, trends are stable, and the spatial correlation among OM incidence, iris color, and rs12913832 may support the role of pigmentation-related risk factors in OM development.

Prevalence estimate of sphingosine phosphate lyase insufficiency syndrome in worldwide and select populations

PurposeSphingosine phosphate lyase insufficiency syndrome (SPLIS) is a rare, often fatal, metabolic disorder and monogenic form of steroid-resistant nephrotic syndrome. Other manifestations include primary adrenal insufficiency, ichthyosis, and neurological defects. SPLIS is caused by biallelic pathogenic variants in SGPL1, encoding sphingosine-1-phosphate lyase, a pyridoxal 5'-phosphate-dependent enzyme that catalyzes the final step of sphingolipid metabolism. Treatment is primarily supportive, but pyridoxine supplementation may be therapeutic in some cases, and gene therapy is being explored. We sought to determine the prevalence of SPLIS globally and among different populations to facilitate patient finding in anticipation of SPLIS clinical trials. MethodsUsing publicly available genomic data sets, including Genome Aggregation Database (gnomAD) v.2.1.1 and gnomAD v3.1.2, Iranome, IndiGen, and private genomic data sets from Israeli, Saudi, South Dakota Hutterite, and Turkish populations, we estimated SPLIS prevalence based on cumulative variant allele frequencies for high-confidence pathogenic variants. SPLIS prevalence estimates were adjusted by the level of inbreeding when the inbreeding coefficient was known. A Bayesian point estimate and 95% credible interval for worldwide SPLIS were calculated based on gnomAD v2.1.1 (GRCh37). ResultsThe SPLIS prevalence estimate based on the total number of samples included from gnomAD v.2.1.1 (n = 141,430) was 0.015/100,000 (95% CI: 0.010 to 0.021). Using additional population data sets, we calculated SPLIS prevalence ranging from 0.046/100,000 to 0.078/100,000 in Turkish and Iranian populations, respectively. ConclusionThe estimated worldwide number of SPLIS individuals is 11,707. Individuals with East Asian, Finnish, Turkish, and Iranian ancestries have an especially high estimated prevalence.

Association of lipid lowering drugs and the risk of systemic lupus erythematosus: a drug target Mendelian randomization.

Background and objective: An interaction between low-density lipoprotein level, lipid-lowering drugs, and systemic lupus erythematosus (SLE) was reported by previous studies. However, whether lipid-lowering drugs provided protective effect for reducing the risk of SLE was unclear. We aimed to clarify this causal relationship through a drug-target Mendelian randomization (MR) study. Methods: Genetic instruments-single nucleotide polymorphism (SNPs)-were utilized to proxy inhibition of the three genes-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), proprotein convertase subtilisin/kexin type 9 (PCSK9), and Niemann-Pick C1-Like 1(NPC1L1), which was corresponded to three lipid-lowering drugs-statins, evolocumab, and ezetimibe. Low-density lipoprotein (LDL) cholesterol was selected as the biomarker for the measurement of the inhibitors of HMGCR, PCSK9, and NPC1L1, and the genetic data were acquired from the Global Lipids Genetics Consortium, which consisted of 1.3 million participants of European ancestry and 146.5 thousand participants of East Asian ancestry. The genetic dataset of SLE was acquired from two large-scale GWAS studies; one recruited 23,210 participants (7,219 SLE cases and 15,991 controls) of European ancestry and the other one recruited 12,653 participants (4,222 SLE cases and 8,431 controls) of Chinese ancestry. The primary analysis used the inverse variance weighted (IVW) method. Four additional sensitivity analyses, colocalization analysis, and stratification analysis were performed. Results: The primary analysis showed that inhibition of PCSK9 (evolocumab) was associated with a significantly lower risk of SLE [odds ratio (OR) 0.51, 95%CI 0.34 to 0.76, p = 0.001] in the European population. The secondary analyses had similar findings. Stratification analysis demonstrated that the preventive effect of PCSK9 inhibition for SLE was similar in both males and females. However, the results were not replicated in the East Asian population. The inhibition of HMGCR (statins) and NPC1L1 (ezetimibe) did not cause a lower risk of SLE. Conclusion: Evolocumab might provide a protective effect on the risk of SLE in the European population, but statins and ezetimibe might not have the protective effect. Further research is necessary to elucidate the specific mechanisms and potential therapeutic applications of PCSK9 inhibitors (evolocumab) in the context of SLE protection.

A large-scale microRNA transcriptome-wide association study identifies two susceptibility microRNAs, miR-1307-5p and miR-192-3p, for colorectal cancer risk.

Transcriptome-wide association studies (TWAS) have identified many putative susceptibility genes for colorectal cancer (CRC) risk. However, susceptibility miRNAs, critical dysregulators of gene expression, remain unexplored. We genotyped DNA samples from 313 CRC East Asian patients and performed small RNA sequencing in their normal colon tissues distant from tumors to build genetic models for predicting miRNA expression. We applied these models and data from genome-wide association studies (GWAS) including 23 942 cases and 217 267 controls of East Asian ancestry to investigate associations of predicted miRNA expression with CRC risk. Perturbation experiments separately by promoting and inhibiting miRNAs expressions and further in vitro assays in both SW480 and HCT116 cells were conducted. At a Bonferroni-corrected threshold of P < 4.5 × 10-4, we identified two putative susceptibility miRNAs, miR-1307-5p and miR-192-3p, located in regions more than 500kb away from any GWAS-identified risk variants in CRC. We observed that a high predicted expression of miR-1307-5p was associated with increased CRC risk, while a low predicted expression of miR-192-3p was associated with increased CRC risk. Our experimental results further provide strong evidence of their susceptible roles by showing that miR-1307-5p and miR-192-3p play a regulatory role, respectively, in promoting and inhibiting CRC cell proliferation, migration, and invasion, which was consistently observed in both SW480 and HCT116 cells. Our study provides additional insights into the biological mechanisms underlying CRC development.

Genetic influences on alcohol flushing in East Asian populations

BackgroundAlthough it is known that variation in the aldehyde dehydrogenase 2 (ALDH2) gene family influences the East Asian alcohol flushing response, knowledge about other genetic variants that affect flushing symptoms is limited.MethodsWe performed a genome-wide association study meta-analysis and heritability analysis of alcohol flushing in 15,105 males of East Asian ancestry (Koreans and Chinese) to identify genetic associations with alcohol flushing. We also evaluated whether self-reported flushing can be used as an instrumental variable for alcohol intake.ResultsWe identified variants in the region of ALDH2 strongly associated with alcohol flushing, replicating previous studies conducted in East Asian populations. Additionally, we identified variants in the alcohol dehydrogenase 1B (ADH1B) gene region associated with alcohol flushing. Several novel variants were identified after adjustment for the lead variants (ALDH2-rs671 and ADH1B-rs1229984), which need to be confirmed in larger studies. The estimated SNP-heritability on the liability scale was 13% (S.E. = 4%) for flushing, but the heritability estimate decreased to 6% (S.E. = 4%) when the effects of the lead variants were controlled for. Genetic instrumentation of higher alcohol intake using these variants recapitulated known associations of alcohol intake with hypertension. Using self-reported alcohol flushing as an instrument gave a similar association pattern of higher alcohol intake and cardiovascular disease-related traits (e.g. stroke).ConclusionThis study confirms that ALDH2-rs671 and ADH1B-rs1229984 are associated with alcohol flushing in East Asian populations. Our findings also suggest that self-reported alcohol flushing can be used as an instrumental variable in future studies of alcohol consumption.

Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease

Thyroid hormones play a critical role in regulation of multiple physiological functions and thyroid dysfunction is associated with substantial morbidity. Here, we use electronic health records to undertake a genome-wide association study of thyroid-stimulating hormone (TSH) levels, with a total sample size of 247,107. We identify 158 novel genetic associations, more than doubling the number of known associations with TSH, and implicate 112 putative causal genes, of which 76 are not previously implicated. A polygenic score for TSH is associated with TSH levels in African, South Asian, East Asian, Middle Eastern and admixed American ancestries, and associated with hypothyroidism and other thyroid disease in South Asians. In Europeans, the TSH polygenic score is associated with thyroid disease, including thyroid cancer and age-of-onset of hypothyroidism and hyperthyroidism. We develop pathway-specific genetic risk scores for TSH levels and use these in phenome-wide association studies to identify potential consequences of pathway perturbation. Together, these findings demonstrate the potential utility of genetic associations to inform future therapeutics and risk prediction for thyroid diseases.

Genomic ancestry in kidney cancer: Correlations with clinical and molecular features.

Genetic ancestry (GA) refers to population hereditary patterns that contribute to phenotypic differences seen among race/ethnicity groups, and differences among GA groups may highlight unique biological determinants that add to our understanding of health care disparities. A retrospective review of patients with renal cell carcinoma (RCC) was performed and correlated GA with clinicopathologic, somatic, and germline molecular data. All patients underwent next-generation sequencing of normal and tumor DNA using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets, and contribution of African (AFR), East Asian (EAS), European (EUR), Native American, and South Asian (SAS) ancestry was inferred through supervised ADMIXTURE. Molecular data was compared across GA groups by Fisher exact test and Kruskal-Wallis test. In 953 patients with RCC, the GA distribution was: EUR (78%), AFR (4.9%), EAS (2.5%), SAS (2%), Native American (0.2%), and Admixed (12.2%). GA distribution varied by tumor histology and international metastatic RCC database consortium disease risk status (intermediate-poor: EUR 58%, AFR 88%, EAS 74%, and SAS 73%). Pathogenic/likely pathogenic germline variants in cancer-predisposition genes varied (16% EUR, 23% AFR, 8% EAS, and 0% SAS), and most occurred in CHEK2 in EUR (3.1%) and FH in AFR (15.4%). In patients with clear cell RCC, somatic alteration incidence varied with significant enrichment in BAP1 alterations (EUR 17%, AFR 50%, SAS 29%; p=.01). Comparing AFR and EUR groups within The Cancer Genome Atlas, significant differences were identified in angiogenesis and inflammatory pathways. Differences in clinical and molecular data by GA highlight population-specific variations in patients with RCC. Exploration of both genetic and nongenetic variables remains critical to optimize efforts to overcome health-related disparities.