Populations Of European Descent Research Articles

Genomic Heritabilities and Correlations of 17 Traits Related to Obesity and Associated Conditions in the Japanese Population.

Over the past few decades, obesity has become a public health issue of global concern. Even though disparities exist between human populations, e.g., the higher liver fat content of the Japanese despite a lower body mass index (BMI), studies on the genetics of obesity still largely focus on populations of European descent, leading to a dearth of genetic data on non-European populations. In this context, this study aimed to establish a broad picture of the genetic attributes of the Japanese population, by examining a representative sample of 18,889 individuals participating in the Tohoku Medical Megabank Project cohort. We applied linear mixed model methods to 17 traits related to obesity and associated diseases to estimate the heritabilities explained by common genetic variants and the genetic correlations between each pair of traits. These analyses allowed us to quantify the SNP heritability of health indicators such as BMI (0.248 ± 0.032) and HDL cholesterol (0.324 ± 0.031), and to provide one of the few estimates of the SNP heritability of cystatin C in unrelated individuals (0.260 ± 0.025). We discuss potential differences between the Japanese and people of European ancestry with respect to the genetic correlations between urinary biomarkers and adiposity traits, for which large estimates were obtained. For instance, the genetic correlations between urine potassium level and the values for weight, BMI, waist circumference, and waist-to-height ratio ranged from 0.290 to 0.559, much higher than the corresponding estimates in the UK Biobank.

Acral lentiginous melanoma: Basic facts, biological characteristics and research perspectives of an understudied disease.

Acral lentiginous melanoma is a histological subtype of cutaneous melanoma that occurs in the glabrous skin of the palms, soles and the nail unit. Although in some countries, particularly in Latin America, Africa and Asia, it represents the most frequently diagnosed subtype of the disease, it only represents a small proportion of melanoma cases in European‐descent populations, which is partially why it has not been studied to the same extent as other forms of melanoma. As a result, its unique genomic drivers remain comparatively poorly explored, as well as its causes, with current evidence supporting a UV‐independent path to tumorigenesis. In this review, we discuss current knowledge of the aetiology and diagnostic criteria of acral lentiginous melanoma, as well as its epidemiological and histopathological characteristics. We also describe what is known about the genomic landscape of this disease and review the available biological models to explore potential therapeutic targets.

1460-P: Type 2 Diabetes Polygenic Score in Addition to Clinical Factors for Prediction of Diabetes Incidence in an Indigenous American Population

Background: Type 2 diabetes (T2D)-associated variants, derived from genome-wide association studies (GWAS), have largely been reproducible across populations, but there is limited information on how polygenic scores (PS) based on these variants add to clinical factors for predicting diabetes incidence, particularly in non-European populations. Methods: A longitudinal study of diabetes was conducted in an Indigenous study population native to the Southwestern U.S. At each exam, a 75-g oral glucose tolerance test was administered with measurement of fasting and 2-hour plasma glucose (FPG, 2hPG). Genotypes were available from a GWAS for 2783 participants aged ≥ 20 years without diabetes at baseline, with imputed genotypes based on whole genome sequence data from 296 individuals from the population. PSs for participants were constructed and weighted using genome-wide significant variants in a T2D GWAS meta-analysis in European-descent populations (n=245; Mahajan 2018). Survival analyses were conducted to predict diabetes incidence in 2 models: (1) age, sex, BMI, FPG; (2) age, sex, BMI, FPG, T2D PS. Area under the receiver-operating characteristic curve (AUC) was calculated using a nonparametric method for survival analysis. Results: 903 cases (32.5%) of diabetes occurred during 25,110 person-years of follow-up. The hazard ratio for T2D PS, controlled for age, sex, BMI and FPG, was 1.27 per SD (P=1.5×10-12). Cumulative incidence at 10 years was 0.076 in the lowest quartile for the prediction score based on clinical factors alone and 0.509 in the highest quartile. For the model including PS, corresponding values were 0.075 and 0.524. AUC was 0.710 for the model with clinical factors alone and 0.721 for the model including T2D PS. Conclusion: Weighted T2D PSs based on 245 variants were informative in predicting T2D incidence in Indigenous Americans; however, the improvement in prediction beyond clinical factors alone was modest. Disclosure L.E. Wedekind: None. S. Kobes: None. W. Hsueh: None. L. Baier: None. W.C. Knowler: None. A. Mahajan: None. M.I. McCarthy: Advisory Panel; Self; Illumina. Consultant; Self; Eli Lilly and Company, Novo Nordisk Inc., Zoe Global Ltd. Employee; Self; Genentech, Inc. Research Support; Self; AbbVie Inc., Merck & Co., Inc., Sanofi-Aventis, Servier, Takeda UK. R.L. Hanson: None.

Development and Validation of Skinfold-Thickness Equations for Predicting Body Fatness in Ethiopian Adults

Abstract Objectives Both body fat and lean body mass have important roles in health and wellbeing. It is crucial that researchers and clinicians can accurately measure them, especially in nutritionally vulnerable populations such as people living in rural areas of Ethiopia. Skinfold thickness measurements are one of the few methods to measure % body fat outside of a clinical setting. The validity of the measurements is dependent upon age, sex, and ethnicity. The existing skinfold thickness equations are derived from populations of European descent. This study will demonstrate that existing equations are not valid for Ethiopian adults and create new, sex-specific equations for this population. Methods Skinfold thickness will be measured on 250 adults recruited from Jimma City, Ethiopia. Percent body fat will be calculated using several existing skinfold thickness equations. For women, the equations are the Sloan; Jackson, Pollock, & Ward; and Durnin and Wormsley. The equations for men are Sloan; Jackson and Pollock; and Durnin and Wormsley. The results of these equations will then be compared against % body fat measured by a BodPod. Pearson's correlation coefficient and Bland-Altman plots will be used to assess the validity of each calculation. Stepwise forward regression will be used to determine new sex-specific equations. Results In women, the Sloan equation had moderate correlation (0.59) while Jackson, Pollack, and Ward and the Durnin and Wormsley equations had near-perfect correlation (0.81 and 0.88 respectively). In men, the Sloan equation had substantial correlation (0.79) while the Jackson and Pollack and the Durnin and Wormsley had near-perfect correlation (0.89 and 0.85 respectively). Scatter and Bland Altman plots showed that all equations underestimated the % body fat measured compared to a BodPod requiring new equations. For women: body density = 1.068892 − 0.00088 x −0.0005412 y − 0.0012765 z. Where x is the skinfold thickness at the suprailiac crest, y is thigh, and x is subscapular. For men: body density = 1.08899 −0.0014585 m −0.0008318 n. Where m is abdominal skinfold thickness and n is thigh skinfold thickness. Conclusions The current most commonly used skinfold thickness equations are not valid for use in Ethiopian adults. The equations put forth in this analysis should be used for this population. Funding Sources H.E. Babcock Fund, NIDDK/NIH.

The monogenic basis of human tuberculosis.

The pathogenesis of tuberculosis (TB) remains poorly understood, as no more than 5-10% of individuals infected with Mycobacterium tuberculosis go on developing clinical disease. The contribution of human genetics to TB pathogenesis has been amply documented by means of classic genetics since the turn of the twentieth century. Over the last 20years, following-up on the study of Mendelian susceptibility to mycobacterial disease (MSMD), monogenic disorders have been found to underlie TB in some patients. Rare inborn errors of immunity, such as autosomal recessive, complete IL-12Rβ1 and TYK2 deficiencies, impairing the IL-12- and IL-23-dependent induction of IFN-γ, were initially identified in a few patients. More recently, homozygosity for a common variant of TYK2 (P1104A) that selectively disrupts cellular responses to IL-23 was found in two cohorts of TB patients. It shows high penetrance in areas endemic for TB and appears to be responsible for about 1% of TB cases in populations of European descent. Both rare and common genetic etiologies of TB affect IFN-γ immunity, providing a rationale for novel preventive and therapeutic approaches for TB control, including the use of recombinant IFN-γ.

Effects of Genetic Variants on Stroke Risk.

Effects of Genetic Variants on Stroke Risk.

African schizophrenia genetic variants

Human Genetics The genetics of schizophrenia have predominately been studied in populations of European and Asian descent. However, studies in Africans, who host the greatest degree of human genetic diversity, have lagged. Examining the exomes of more than 1800 Xhosa individuals from South Africa, about half of which have been diagnosed with schizophrenia, Gulsuner et al. identified both rare and common genetic variants associated with the disease. They found that the genetic architecture of schizophrenia in Africans generally reflects that of Europeans but that the greater genetic variation in Africa provides more power to detect relationships of genes to phenotypes. Science , this issue p. [569][1] [1]: /lookup/doi/10.1126/science.aay8833

Distribution of allele frequencies for genes associated with physical activity and/or physical capacity in a homogenous Norwegian cohort- a cross-sectional study

BackgroundThere are large individual differences in physical activity (PA) behavior as well as trainability of physical capacity. Heritability studies have shown that genes may have as much impact on exercise participation behavior as environmental factors. Genes that favor both trainability and participation may increase the levels of PA. The present study aimed to assess the allele frequencies in genes associated with PA and/or physical capacity, and to see if there is any association between these polymorphisms and self-reported PA levels in a cohort of middle-aged Norwegians of Scandinavian descent (n = 831; mean age mean age (± SD) 55.5 ± 3.8 years).ResultsThe genotype distributions of the ACTN3 R577X, ACE I/D and MAOA uVNTR polymorphisms were similar to other populations of European descent. When comparing the genotype distribution between the low/medium level PA group (LMPA) and high level PA groups (HPA), a significant difference in ACTN3 577X allele distribution was found. The X allele frequency was 10% lower in the HPA level group (P = 0.006). There were no differences in the genotype distribution of the ACE I/D or MAOA uVNTR polymorphism. Education and previous participation in sports or outdoor activities was positively associated with the self-reported PA levels (P ≤ 0.001).ConclusionsTo the best of our knowledge, this is the first study to report association between ACTN3 R577X genotype and PA level in middle-aged Scandinavians. Nevertheless, the contribution of a single polymorphism to a complex trait, like PA level, is likely small. Socioeconomic variables, as education and previous participation in sports or outdoor activities, are positively associated with the self-reported PA levels.

Genome-wide association study in Chinese cohort reveals a new susceptibility locus within the 12q13.13 region for hypospadias

Hypospadias risk–associated gene variants have been reported in populations of European descent using genome-wide association studies (GWAS). There is little known at present about any possible hypospadias risk associations in Han Chinese populations. To systematically investigate hypospadias risk–associated gene variants in Chinese patients, we performed the first GWAS in a Han Chinese cohort consisting of 200 moderate-severe hypospadias cases and 1008 unaffected controls. Suggestive loci (p<1×10−4) were replicated in 118 cases and 383 controls, as well as in a second independent validation population of 137 cases and 190 controls. Regulatory were then conducted for the functional analyses of candidate variants. We identified rs11170516 with the risk allele G within the SP1/SP7 region that was independently associated with moderate-severe Hypospadias [SP1/SP7, rs11170516, Pcombine = 3.5×10-9, odds ratio (OR) = 1.96 (1.59-2.44)]. Results also suggested that rs11170516 is associated with the expression of SP1 as a cis-expression quantitative trait loci (cis-eQTL). We performed the first GWAS of moderate-severe hypospadias in a Han Chinese cohort, and identified one novel susceptibility cis-acting regulatory locus at 12q13.13, which may regulate a variety of hypospadias-related pathways by affecting proximal SP1 gene expression. This study complements known common hypospadias risk-associated variants and provides the possible role of cis-acting regulatory variant in causing hypospadias.

Chinese Society of Allergy and Chinese Society of Otorhinolaryngology-Head and Neck Surgery Guideline for Chronic Rhinosinusitis.

The current document is based on a consensus reached by a panel of experts from the Chinese Society of Allergy and the Chinese Society of Otorhinolaryngology-Head and Neck Surgery, Rhinology Group. Chronic rhinosinusitis (CRS) affects approximately 8% of Chinese adults. The inflammatory and remodeling mechanisms of CRS in the Chinese population differ from those observed in the populations of European descent. Recently, precision medicine has been used to treat inflammation by targeting key biomarkers that are involved in the process. However, there are no CRS guidelines or a consensus available from China that can be shared with the international academia. The guidelines presented in this paper cover the epidemiology, economic burden, genetics and epigenetics, mechanisms, phenotypes and endotypes, diagnosis and differential diagnosis, management, and the current status of CRS in China. These guidelines—with a focus on China—will improve the abilities of clinical and medical staff during the treatment of CRS. Additionally, they will help international agencies in improving the verification of CRS endotypes, mapping of eosinophilic shifts, the identification of suitable biomarkers for endotyping, and predicting responses to therapies. In conclusion, these guidelines will help select therapies, such as pharmacotherapy, surgical approaches and innovative biotherapeutics, which are tailored to each of the individual CRS endotypes.

Genetic and polygenic risk score analysis for Alzheimer's disease in the Chinese population.

IntroductionDozens of Alzheimer's disease (AD)‐associated loci have been identified in European‐descent populations, but their effects have not been thoroughly investigated in the Hong Kong Chinese population.MethodsTaqMan array genotyping was performed for known AD‐associated variants in a Hong Kong Chinese cohort. Regression analysis was conducted to study the associations of variants with AD‐associated traits and biomarkers. Lasso regression was applied to establish a polygenic risk score (PRS) model for AD risk prediction.Results SORL1 is associated with AD in the Hong Kong Chinese population. Meta‐analysis corroborates the AD‐protective effect of the SORL1 rs11218343 C allele. The PRS is developed and associated with AD risk, cognitive status, and AD‐related endophenotypes. TREM2 H157Y might influence the amyloid beta 42/40 ratio and levels of immune‐associated proteins in plasma.Discussion SORL1 is associated with AD in the Hong Kong Chinese population. The PRS model can predict AD risk and cognitive status in this population.

A phenome-wide association study (PheWAS) in the Population Architecture using Genomics and Epidemiology (PAGE) study reveals potential pleiotropy in African Americans.

We performed a hypothesis-generating phenome-wide association study (PheWAS) to identify and characterize cross-phenotype associations, where one SNP is associated with two or more phenotypes, between thousands of genetic variants assayed on the Metabochip and hundreds of phenotypes in 5,897 African Americans as part of the Population Architecture using Genomics and Epidemiology (PAGE) I study. The PAGE I study was a National Human Genome Research Institute-funded collaboration of four study sites accessing diverse epidemiologic studies genotyped on the Metabochip, a custom genotyping chip that has dense coverage of regions in the genome previously associated with cardio-metabolic traits and outcomes in mostly European-descent populations. Here we focus on identifying novel phenome-genome relationships, where SNPs are associated with more than one phenotype. To do this, we performed a PheWAS, testing each SNP on the Metabochip for an association with up to 273 phenotypes in the participating PAGE I study sites. We identified 133 putative pleiotropic variants, defined as SNPs associated at an empirically derived p-value threshold of p<0.01 in two or more PAGE study sites for two or more phenotype classes. We further annotated these PheWAS-identified variants using publicly available functional data and local genetic ancestry. Amongst our novel findings is SPARC rs4958487, associated with increased glucose levels and hypertension. SPARC has been implicated in the pathogenesis of diabetes and is also known to have a potential role in fibrosis, a common consequence of multiple conditions including hypertension. The SPARC example and others highlight the potential that PheWAS approaches have in improving our understanding of complex disease architecture by identifying novel relationships between genetic variants and an array of common human phenotypes.

Genome-wide association study in Chinese cohort identifies one novel hypospadias risk associated locus at 12q13.13

BackgroundHypospadias risk–associated gene variants have been reported in populations of European descent using genome-wide association studies (GWASs). There is little known at present about any possible hypospadias risk associations in Han Chinese populations.MethodsTo systematically investigate hypospadias risk–associated gene variants in Chinese patients, we performed the first GWAS in a Han Chinese cohort consisting of 197 moderate-severe hypospadias cases and 933 unaffected controls. Suggestive loci (p < 1 × 10− 4) were replicated in 118 cases and 383 controls, as well as in a second independent validation population of 137 cases and 190 controls. Regulatory and protein-protein interactions (PPIs) were then conducted for the functional analyses of candidate variants.ResultsWe identified rs11170516 with the risk allele G within the SP1/SP7 region that was independently associated with moderate-severe hypospadias [SP1/SP7, rs11170516, Pcombine = 3.5 × 10− 9, odds ratio (OR) = 1.96 (1.59–2.44)]. Results also suggested that rs11170516 is associated with the expression of SP1 as a cis-expression quantitative trait locus (cis-eQTL). Protein SP1 could affect the risk of hypospadias via PPIs.ConclusionsWe performed the first GWAS of moderate-severe hypospadias in a Han Chinese cohort, and identified one novel susceptibility cis-acting regulatory locus at 12q13.13, which may regulate a variety of hypospadias-related pathways by affecting proximal SP1 gene expression and subsequent PPIs. This study complements known common hypospadias risk-associated variants and provides the possible role of cis-acting regulatory variant in causing hypospadias.

Recurrent PTPRT/JAK2 mutations in lung adenocarcinoma among African Americans

Reducing or eliminating persistent disparities in lung cancer incidence and survival has been challenging because our current understanding of lung cancer biology is derived primarily from populations of European descent. Here we show results from a targeted sequencing panel using NCI-MD Case Control Study patient samples and reveal a significantly higher prevalence of PTPRT and JAK2 mutations in lung adenocarcinomas among African Americans compared with European Americans. This increase in mutation frequency was validated with independent WES data from the NCI-MD Case Control Study and TCGA. We find that patients carrying these mutations have a concomitant increase in IL-6/STAT3 signaling and miR-21 expression. Together, these findings suggest the identification of these potentially actionable mutations could have clinical significance for targeted therapy and the enrollment of minority populations in clinical trials.

Local ancestry at APOE modifies Alzheimer's disease risk in Caribbean Hispanics

IntroductionAlthough the relationship between APOE and Alzheimer's disease (AD) is well established in populations of European descent, the effects of APOE and ancestry on AD risk in diverse populations is not well understood. MethodsLogistic mixed model regression and survival analyses were performed in a sample of 3067 Caribbean Hispanics and 3028 individuals of European descent to assess the effects of APOE genotype, local ancestry, and genome-wide ancestry on AD risk and age at onset. ResultsAmong the Caribbean Hispanics, individuals with African-derived ancestry at APOE had 39% lower odds of AD than individuals with European-derived APOE, after adjusting for APOE genotype, age, and genome-wide ancestry. While APOE E2 and E4 effects on AD risk and age at onset were significant in the Caribbean Hispanics, they were substantially attenuated compared with those in European ancestry individuals. DiscussionThese results suggest that additional genetic variation in the APOE region influences AD risk beyond APOE E2/E3/E4.

Genome-wide Association Studies in Ancestrally Diverse Populations: Opportunities, Methods, Pitfalls, and Recommendations.

Genome-wide association studies (GWASs) have focused primarily on populations of European descent, but it is essential that diverse populations become better represented. Increasing diversity among study participants will advance our understanding of genetic architecture in all populations and ensure that genetic research is broadly applicable. To facilitate and promote research in multi-ancestry and admixed cohorts, we outline key methodological considerations and highlight opportunities, challenges, solutions, and areas in need of development. Despite the perception that analyzing genetic data from diverse populations is difficult, it is scientifically and ethically imperative, and there is an expanding analytical toolbox to do it well.

Orthodontic treatment with removal of one mandibular incisor: Outcome data and the importance of extraction site preparation

Extraction of one mandibular incisor in adolescents and adults can simplify orthodontic treatment in 2 major circumstances: (1) severe crowding of the mandibular but not the maxillary incisors, and (2) mild anterior crossbite with good alignment in both arches. Despite its potential advantages, this method has had limited use in most practices. There have been 3 major objections: (1) the possibility of unsightly black triangles because of loss of interdental papilla height, (2) a possible tooth size discrepancy that would affect occlusal relationships, and (3) patient concerns about a visible extraction site. All 3 objections now can be overcome. For 37 consecutively treated single-incisor-extraction patients, preparation of the extraction site for the tooth to be extracted was done by tipping it lingually while simultaneously closing the space in front of it. Treatment outcomes and the effect of age at the time of treatment were evaluated. In patients below age 20, this approach eliminated post-treatment black triangles and almost eliminated partial loss of the interdental papilla. It reduced the previously reported prevalence of these problems in patients aged 20-40years and did not seem to be helpful in those aged over 40years. This positive effect was achieved because of maintenance of alveolar crest height that supports the interdental papillae. Tooth size discrepancy caused by incisor extraction was largely compensated by the different labio-lingual orientation of maxillary and mandibular anterior teeth. The extraction space quickly disappeared during extraction site preparation. The new procedure of extraction site preparation described in this paper offers more favorable outcomes for post-treatment prevalence of black triangles in younger patients but shows limited efficacy in older patients. Camouflage of a mild skeletal Class III problem is the major indication for this extraction pattern. About 3% of Icelandic orthodontic patients appear to be good candidates for this treatment, and this finding should be reasonably generalizable to other populations of European descent.

Transcriptome association studies of neuropsychiatric traits in African Americans implicate PRMT7 in schizophrenia.

In the past 15 years, genome-wide association studies (GWAS) have provided novel insight into the genetic architecture of various complex traits; however, this insight has been primarily focused on populations of European descent. This emphasis on European populations has led to individuals of recent African descent being grossly underrepresented in the study of genetics. With African Americans making up less than 2% of participants in neuropsychiatric GWAS, this discrepancy is magnified in diseases such as schizophrenia and bipolar disorder. In this study, we performed GWAS and the gene-based association method PrediXcan for schizophrenia (n = 2,256) and bipolar disorder (n = 1,019) in African American cohorts. In our PrediXcan analyses, we identified PRMT7 (P = 5.5 × 10−6, local false sign rate = 0.12) as significantly associated with schizophrenia following an adaptive shrinkage multiple testing adjustment. This association with schizophrenia was confirmed in the much larger, predominantly European, Psychiatric Genomics Consortium. In addition to the PRMT7 association with schizophrenia, we identified rs10168049 (P = 1.0 × 10−6) as a potential candidate locus for bipolar disorder with highly divergent allele frequencies across populations, highlighting the need for diversity in genetic studies.

The effect of exercise training on blood pressure in African and Asian populations: A systematic review and meta-analysis of randomized controlled trials.

Exercise is key in the primary prevention and management of hypertension. Yet, current exercise recommendations are predominantly based on meta-analyses involving populations of European descent. Since blood pressure (BP) responses to pharmaceutical interventions are known to differ among ethnic groups, we aimed to investigate the BP responses to exercise training in non-European descendants. The aim of this study was to systematically summarize the available literature on the efficacy of exercise on BP in healthy adults (age ≥18 years) of African or Asian origin. We searched the MEDLINE database for randomized controlled trials that evaluated the effect of exercise training on BP in healthy African and Asian adults with optimal BP, elevated BP or hypertension and published in a peer-reviewed journal up to May 2019. Random effect models were fitted to estimate the effect sizes. We identified 22 trials involving individuals of Asian origin (n = 931; mean age: 44 years; 41% male) and four trials involving individuals of African origin (n = 510; mean age: 56.7 years; 80% male). Aerobic exercise training significantly (p < 0.001) reduced systolic and diastolic BP in each ethnic group. Resistance training did not affect the BP of Asian participants with optimal BP. The effect of resistance training in Asians with elevated BP or hypertension and Africans could not be determined due to lack of data. Sub-analyses suggested somewhat larger reductions in systolic BP following aerobic training in hypertensive Africans compared with hypertensive Asians. We found favorable effects of aerobic exercise training on BP in the African and the Asian populations. However, the overall low number of studies and especially the lack of data on resistance training and combined training in African and Asian populations warrant more research to improve the quality of evidence.

Population-specific long-range linkage disequilibrium in the human genome and its influence on identifying common disease variants

Despite the availability of large-scale sequencing data, long-range linkage disequilibrium (LRLD) has not been extensively studied. The theoretical aspects of LRLD estimates were studied to determine the best estimation method for the sequencing data of three different populations of African (AFR), European (EUR), and East-Asian (EAS) descent from the 1000 Genomes Project. Genome-wide LRLDs excluding centromeric regions revealed clear population specificity, presenting substantially more population-specific LRLDs than coincident LRLDs. Clear relationships between the functionalities of the regions in LRLDs denoted long-range interactions in the genome. The proportions of gene regions were increased in LRLD variants, and the coding sequence (CDS)-CDS LRLDs showed obvious functional similarities between genes in LRLDs. Application to theoretical case-control associations confirmed that the LRLDs in genome-wide association studies (GWASs) could contribute to false signals, although the impacts might not be severe in most cases. LRLDs with variants with functional similarity exist in the human genome indicating possible gene-gene interactions, and they differ depending on populations. Based on the current study, LRLDs should be examined in GWASs to identify true signals. More importantly, population specificity in LRLDs should be examined in relevant studies.