Populations Of European Ancestry Research Articles

Abstract 3631: Transcriptome-wide association study identifies novel genes associated with breast cancer susceptibility in Latinas

Abstract Background: Genetic susceptibility to breast cancer has been studied extensively in European ancestry populations, but few studies have addressed genetic susceptibility in non-European women. Latinas are a genetically diverse group with contributions from European, African, and Indigenous American ancestries. Genome-wide association studies (GWAS) have identified unique variants in this population, particularly at the 6q25 locus. We conducted a transcriptome-wide association study (TWAS) to identify novel genes associated with risk of breast cancer in Latinas. Methods: We used individual level GWAS data from 2,396 Latina cases and 6,505 Latina controls from the studies in Northern California (San Francisco Bay Area Breast Cancer Study, Northern California Breast Cancer Family Registry and Kaiser Permanente Genetic Epidemiology Research on Aging Cohort), Southern California (Multi-ethnic Cohort) and Mexico (CAMA study). We analyzed the association between genetically predicted whole blood (WB) gene expression and breast cancer risk using newly developed TWAS models based on 784 Mexican American individuals. We also conducted parallel analyses using breast mammary tissue (BT) TWAS models from GTEx v8. All analyses were adjusted for age, ancestry, and study. Associations with false discovery rate (FDR) probability <0.05 were considered statistically significant. Results: At FDR<0.05, we identified 20 genes from BT and 39 genes from WB. Seven of the genes were significantly associated in both the WB models and GTEx BT models. Increased expression of MIB2 (pFDR = 4.74x10-17 (WB) and 1.22x10-4 (BT)), NBPF26 (pFDR = 1.30x10-7 (WB) and 7.43x10-8 (BT)), SLC35E2B (pFDR = 1.12x10-4 (WB) and 5.47x10-5 (BT)), and FAM30A (pFDR = 1.18x10-10 (WB) and 9.27x10-3 (BT)) was associated with increased risk of breast cancer risk, whereas increased expression of SLC35E2A (pFDR = 8.17x10-6 (WB) and 1.55x10-3 (BT)) and HCP5B (pFDR = 1.84x10-3 (WB) and 2.19x10-3 (BT)) was associated with decreased breast cancer risk. Increased expression of PDGFA was associated with increased risk (pFDR = 1.30x10-7) in GTEx BT reference models but decreased risk (pFDR = 2.34x10-10) in the ancestry-specific WB model. Conclusion: Our study is the first TWAS investigating the relationship between genetically predicted gene expression and breast cancer risk in Latinas. By leveraging gene expression prediction models that capture eQTLs that are more common in populations with Indigenous American ancestry, we have identified some novel genes associated with breast cancer risk in Latinas. Of these, MIB2 is a strong candidate for a mechanistic role in breast carcinogenesis in Latinas. MIB2 is involved in Notch signaling which plays an important role in breast carcinogenesis via its mismatched receptor-ligand interaction. Our study highlights the role of ancestry-based prediction models in TWAS analyses. Citation Format: Pooja Middha Kapoor, Angel C. Mak, Linda Kachuri, Donglei Hu, Scott Huntsman, Lawrence H. Kushi, Christopher Haiman, Esther M. John, Gabriela Torres-Mejia, Esteban G. Burchard, Susan L. Neuhausen, Laura Fejerman, Elad Ziv. Transcriptome-wide association study identifies novel genes associated with breast cancer susceptibility in Latinas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3631.

Abstract 5903: Polygenic risk scores for prediction of breast cancer in Korean women

Abstract Background: Polygenic risk scores (PRS) developed in large European GWAS have been shown to perform well in Asian women relative to PRS developed in smaller Asian studies. However, prospective validation of absolute risk prediction models combining lifestyle and PRS in Asian women is limited. We evaluate the calibration of four PRS developed using Asian or European training samples; two PRS were restricted to genome-wide significant SNPs (GRS-11ASN, GRS-136EUR) and two included sub-genome-wide significant SNPs (PRS-42ASN, PRS-209EUR). Methods: For each PRS, we compared discrimination (area under the curve [AUC]) and calibration (expected-to-observed ratio [E/O]) of three absolute risk models among 41,031 women from the Korean Cancer Prevention Study-II Biobank: (i) a model using incidence, mortality, and risk factor distributions (reference inputs) among U.S. women and European relative risks; (ii) a recalibrated model, using Korean reference but European relative risks; and (iii) a fully Korean-based model using Korean reference and relative risk estimates from KCPS. Results: All Asian and European PRS improved risk prediction for breast cancer in Korean women (Qx: AUC=0.65, Qx+PRS-42ASN: AUC=0.68, Qx+PRS-209EUR: AUC=0.69 in Korean-based model for age less than 50). We found that the U.S.-based absolute risk models overestimated the risks for women age ≥50 years (PRS-42ASN: E/O=1.93, 95% CI=1.69, 2.19, PRS-209EUR: E/O = 1.92, 95% CI=1.69, 2.19). Our absolute risk projections suggest that risk-reducing lifestyle changes would lead to larger absolute risk reductions among women at higher PRS. Conclusions: Incorporation of PRS previously developed in Asian and European-ancestry populations can improve discrimination in Korean women. Our finding suggests that PRS may be useful for prioritizing individuals for targeted intervention on their lifestyle such as alcohol intake and obesity. Larger Asian training samples should improve PRS discrimination among Korean women. Further studies are needed to evaluate the value of incorporating additional information on factors into a model in ancestrally diverse populations. Citation Format: Yon Ho Jee, Weang-Kee Ho, Sohee Park, Douglas Easton, Soo-Hwang Teo, Keum Ji Jung, Peter Kraft. Polygenic risk scores for prediction of breast cancer in Korean women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5903.

Abstract 5871: Genome wide association study of breast density among women of African ancestry

Abstract Introduction & Purpose: Breast density, the relative amount of fibroglandular versus fatty tissue in the breast, is one of the strongest breast cancer risk factors. Understanding genetic factors associated with breast density may help clarify mechanisms by which breast density increases breast cancer risk. To date, 46 genetic loci have been associated with breast density, however, these studies have been performed among predominantly European ancestry populations. This study sought to identify genetic factors associated with breast density among women of African ancestry. Methods: We utilized a cohort of women aged 40-85 years who underwent screening mammography at the Hospital of the University of Pennsylvania from 2010-2014. The cohort was linked to the Penn Medicine BioBank (PMBB), a repository of DNA samples from consenting patients. We conducted a genome-wide association study (GWAS) of breast density among women with available genotypes who either self-reported their race as Black/African American, or had an African ancestry genotype (N = 1,323). For each mammogram, the publicly available “LIBRA” software (v1.0.4) was used to quantify dense area and area percent density (dense area divided by breast area) from raw (i.e., FOR PROCESSING) full-field digital mammograms (Selenia Dimensions, Hologic Inc.). Women completed a breast cancer risk factor questionnaire at the time of mammography and BMI was obtained from electronic health records. We tested for associations of dense area and area percent density with ~8.5M common variants, adjusting for age, BMI, menopausal status, and two principle components of ancestry as covariates. Results: We identified three novel loci associated with dense area at genome wide significance (p < 5e-08), including KCNA3 (rs61803939, p =3.40e-08, beta=3.26, SE=0.59) and two nearby loci on chromosome 19, ZNF486 (rs6511094, p =1.41e-08, beta=2.44, SE=0.43) and LOC100129265 (rs1428621382 p = 5.13E-08, beta=2.40, SE=0.44). Our results also replicated three previously reported signals near genes TET3 associated with dense area, TNS1 and SMIM25 associated with area percent density at nominally significant p < 1e-06. Conclusions: To our knowledge, this is the first breast density GWAS in women of African ancestry. Although the study had a small sample size, the analyses replicated associations of three known genes and also identified three novel breast density loci. Notably, variant rs61803939 mapping to KCNA3 gene is present in samples of African ancestry at a higher frequency (MAF=0.14) than in samples of European ancestry (MAF=0.09). Additionally, this variant also has a high oncogenecity score (Phred Score=21.9) and is estimated as likely driver of cancer. Further investigation of the role of variants in KCNA3 in breast density and in influencing the breast cancer risk are warranted, as are larger GWAS evaluating genetic variants for breast density among African ancestry populations. Citation Format: Shefali Verma, Lindsay Guare, Aimilia Gastounioti, Sarah Ehsan, Emily F. Conant, Marylyn Ritchie, Despina Kontos, Anne Marie McCarthy. Genome wide association study of breast density among women of African ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5871.

A monoallelic variant in EYA1 is associated with Branchio-Otic syndrome in a Malian family.

BackgroundBranchio‐otic syndrome (BO) is one of the most common types of syndromic hearing impairment (HI) with an incidence of 1/40,000 globally. It is an autosomal dominant disorder typically characterized by the coexistence of branchial cysts or fistulae, malformations of the external, middle, and inner ears with preauricular pits or tags and a variable degree of HI. Most cases of BO have been reported in populations of European ancestry. To date, only few cases have been reported in people from African descent.MethodsAfter a careful clinical examination, a pure tone audiometry was performed. DNA was extracted from peripheral blood and whole exome, and Sanger sequencing were performed for genetic analysis.ResultsEight individuals from a large non‐consanguineous Malian family, with autosomal dominant inheritance were enrolled. The ages at diagnosis ranged from 8 to 54 years. A high phenotypic variability was noted among the affected individuals. Four patients presented with a post‐lingual and mixed type of HI, one individual had conductive HI while three had normal hearing but presented other BO features namely branchial fistulae and preauricular sinus. Serum creatinine level and renal ultrasonography were normal in three affected individuals who performed them. Genetic testing identified a monoallelic pathogenic variant in EYA1 (c.1286A > G; p.Asp429Gly) segregating with BO syndrome in the family.ConclusionThis is the first genetically confirmed case of BO syndrome caused by EYA1 variant in the sub‐Saharan African population, expanding the genetic spectrum of the condition.

Does a Multiple Myeloma Polygenic Risk Score Predict Overall Survival of Patients with Myeloma?

Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival. We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed. SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P < 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09-1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01-1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant. Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS. This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma.

Cardiovascular health and four epigenetic clocks

BackgroundCardiovascular health (CVH) was defined by the American Heart Association as an integrative idealness of seven clinical or lifestyle factors. Based on populations of European ancestry, recent studies have shown that ideal CVH is associated with a slower aging rate. The aging rate is measured by levels of epigenetic age acceleration (EAA), usually obtained from the residuals of regressing DNA methylation (DNAm) age on chronological age. However, little has been known about the association of CVH with biological aging in Asian populations.Methods and resultsWe here analyzed blood DNAm data and clinical/lifestyle factors of 2474 Taiwan Biobank (TWB) participants, to investigate the association of CVH with EAA. CVH was assessed by seven components: smoking status, physical activity, dietary habits, body mass index, total cholesterol, fasting glucose, and blood pressure levels. Four measures of EAA were applied, among which two were based on the first-generation DNAm clocks (HannumEAA and IEAA) and two were based on the second-generation clocks (PhenoEAA and GrimEAA). After excluding 276 individuals with cardiovascular diseases, we regressed EAA on the CVH score (ranging from 0 to 7, integrating the abovementioned seven components) while adjusting for sex, drinking status, and educational attainment.Our results showed that a decrease in one point in the CVH score was associated with a 0.350-year PhenoEAA (p = 4.5E−4) and a 0.499-year GrimEAA (p = 4.2E−15). By contrast, HannumEAA and IEAA were not significantly associated with the CVH score. We have obtained consistent results within each generation of epigenetic clocks.ConclusionsThis is one of the first studies to comprehensively investigate the associations of CVH with four epigenetic clocks. Our TWB data showed that ideal CVH is associated with lower levels of EAA calculated according to the second-generation epigenetic clocks (PhenoEAA and GrimEAA). Having an ideal CVH status can lower EAA and reduce the risk of aging-related disorders.

Gene-driven Social Connectedness in the Divergence Between East and West

The divergence of Eastern and Western civilizations is conventionally explained by a combination of historical, economical, and geographical factors. Here I explored the contribution of DRD2 and CYP2A6 gene variations, that were shown to contribute to homophily and heterophily in friendship in social networks and differ in their frequencies in East Asia and European ancestry populations. Modeling suggests that allelic frequencies, profoundly affect the abundance of predicted social connections in the two populations: in the European ancestry populations, the total number of predicted connections was almost twofold higher than that of the East Asian population. A plausible hypothesis is that abundant connections between individuals, likely supersede the coherence of hierarchical structures in societies, promoting individualism. In East Asia, the reduced prevalence of DRD2-associated connections favors a more collectivistic society at which the hierarchy is not compromised by the complex interpersonal relationships among individuals. These trends were reenforced by the observation that in the European populations only, the predicted social connections derived by the actual DRD2 genotypes were elevated compared to those calculated by the corresponding frequencies of the DRD2 alleles. The presence of the heterophily-linked CYP2A6 variations in the EUR population may also contribute to this as it may operate as a “social disruptor” gene, conferring to the establishment of relatively isolated clusters, increasing the overall complexity of the resulting social network. These approaches may provide paradigms contributing to our understanding of cultural divergence between populations.

Shared genetic architectures of subjective well-being in East Asian and European ancestry populations.

Subjective well-being (SWB) has been explored in European ancestral populations; however, whether the SWB genetic architecture is shared across populations remains unclear. We conducted a cross-population genome-wide association study for SWB using samples from Korean (n = 110,919) and European (n = 563,176) ancestries. Five ancestry-specific loci and twelve cross-ancestry significant genomic loci were identified. One novel locus (rs12298541 near HMGA2) associated with SWB was also identified through the European meta-analysis. Significant cross-ancestry genetic correlation for SWB between samples was observed. Polygenic risk analysis in an independent Korean cohort (n = 22,455) demonstrated transferability between populations. Significant correlations between SWB and major depressive disorder, and significant enrichment of central nervous system-related polymorphisms heritability in both ancestry populations were found. Hence, large-scale cross-ancestry genome-wide association studies can advance our understanding of SWB genetic architecture and mental health.

The Skin We Live in: Pigmentation Traits and Tanning Behaviour in British Young Adults, an Observational and Genetically-Informed Study.

Skin cancer incidence has been increasing worldwide, representing a particularly high burden for populations of European ancestry. Outdoor and indoor tanning using ultraviolet (UV) radiation devices are major risk factors for skin cancer. While tanning behaviours can be modified by targeted interventions to reduce skin cancer rates, there is insufficient evidence on the motivations for tanning preferences and their relationship with pigmentation phenotypes. The present observational and genetically-informed study investigates motives for tanning and the role that pigmentation phenotypes play on outdoor and indoor tanning behaviour in British young adults. This study included 3722 participants from the Avon Longitudinal Study of Parents and Children in South West England, with data on pigmentation features, tanning ability and preferences, and SNP genotypes. Liking to tan and outdoor tanning were strongly influenced by pigmentary traits and tanning ability. However, the association of these phenotypes with UV indoor tanning was weaker. Our results provide evidence to support the implementation of skin cancer preventative interventions that consider individual biological characteristics and motives for undergoing outdoor and indoor tanning.

Analysis of humeral septal apertures in forensic and archaeological samples

Septal apertures (SA) are defects in the bony septum that separates the olecranon and coronoid fossae. Previous research suggests the presence of SA are highly variable between populations and generally occur at higher frequencies in females and on left humeri. Here, we analyze specimens from two modern willed body forensic collections (n = 617) and three archaeological assemblages (n = 103). Where feasible, we test for differences between sexes, sides, aperture sizes, and age distributions within self-identified racial categories and in the complete assemblage. We also present a novel assessment of SA and handedness. In brief, significant sex-based differences were found in one archaeological sample, the combined forensic sample, and the white racial category. Significant side-based differences favoring the left were found in the combined forensic and male specific sample. Significant differences in SA sizes were identified when bilaterally expressed in the forensic mixed sex sample. A test for aperture presence and hand dominance found significant differences with the majority (71%) of unilateral apertures found on the non-dominant side. Aperture presence was strongly correlated (r > 0.97) with sample size and uncorrelated with age cohorts. While high (> 40%) population-based frequencies were found in the archaeological samples similar to previous studies, a high frequency (17.8%) was also found in the white racial category exceeding most values reported for populations of European ancestry. This study contributes to the understanding of SA by providing a novel analysis of their association with handedness and provides new data on their prevalence in both archaeological and modern forensic assemblages.

The Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations.

Polygenic risk scores (PRSs) aggregate the effects of genetic variants across the genome and are used to predict risk of complex diseases, such as obesity. Current PRSs only include common variants (minor allele frequency (MAF) ≥1%), whereas the contribution of rare variants in PRSs to predict disease remains unknown. Here, we examine whether augmenting the standard common variant PRS (PRScommon) with a rare variant PRS (PRSrare) improves prediction of obesity. We used genome-wide genotyped and imputed data on 451,145 European-ancestry participants of the UK Biobank, as well as whole exome sequencing (WES) data on 184,385 participants. We performed single variant analyses (for both common and rare variants) and gene-based analyses (for rare variants) for association with BMI (kg/m2), obesity (BMI ≥ 30 kg/m2), and extreme obesity (BMI ≥ 40 kg/m2). We built PRSscommon and PRSsrare using a range of methods (Clumping+Thresholding [C+T], PRS-CS, lassosum, gene-burden test). We selected the best-performing PRSs and assessed their performance in 36,757 European-ancestry unrelated participants with whole genome sequencing (WGS) data from the Trans-Omics for Precision Medicine (TOPMed) program. The best-performing PRScommon explained 10.1% of variation in BMI, and 18.3% and 22.5% of the susceptibility to obesity and extreme obesity, respectively, whereas the best-performing PRSrare explained 1.49%, and 2.97% and 3.68%, respectively. The PRSrare was associated with an increased risk of obesity and extreme obesity (ORobesity = 1.37 per SDPRS, P obesity = 1.7x10-85; ORextremeobesity = 1.55 per SDPRS, P extremeobesity = 3.8x10-40), which was attenuated, after adjusting for PRScommon (ORobesity = 1.08 per SDPRS, P obesity = 9.8x10-6; ORextremeobesity= 1.09 per SDPRS, P extremeobesity = 0.02). When PRSrare and PRScommon are combined, the increase in explained variance attributed to PRSrare was small (incremental Nagelkerke R2 = 0.24% for obesity and 0.51% for extreme obesity). Consistently, combining PRSrare to PRScommon provided little improvement to the prediction of obesity (PRSrare AUC = 0.591; PRScommon AUC = 0.708; PRScombined AUC = 0.710). In summary, while rare variants show convincing association with BMI, obesity and extreme obesity, the PRSrare provides limited improvement over PRScommon in the prediction of obesity risk, based on these large populations.

A Large-Scale Genome-Wide Gene-Gene Interaction Study of Lung Cancer Susceptibility in Europeans With a Trans-Ethnic Validation in Asians

IntroductionAlthough genome-wide association studies have been conducted to investigate genetic variation of lung tumorigenesis, little is known about gene-gene (G × G) interactions that may influence the risk of non-small cell lung cancer (NSCLC). MethodsLeveraging a total of 445,221 European-descent participants from the International Lung Cancer Consortium OncoArray project, Transdisciplinary Research in Cancer of the Lung and UK Biobank, we performed a large-scale genome-wide G × G interaction study on European NSCLC risk by a series of analyses. First, we used BiForce to evaluate and rank more than 58 billion G × G interactions from 340,958 single-nucleotide polymorphisms (SNPs). Then, the top interactions were further tested by demographically adjusted logistic regression models. Finally, we used the selected interactions to build lung cancer screening models of NSCLC, separately, for never and ever smokers. ResultsWith the Bonferroni correction, we identified eight statistically significant pairs of SNPs, which predominantly appeared in the 6p21.32 and 5p15.33 regions (e.g., rs521828C6orf10 and rs204999PRRT1, ORinteraction = 1.17, p = 6.57 × 10−13; rs3135369BTNL2 and rs2858859HLA-DQA1, ORinteraction = 1.17, p = 2.43 × 10−13; rs2858859HLA-DQA1 and rs9275572HLA-DQA2, ORinteraction = 1.15, p = 2.84 × 10−13; rs2853668TERT and rs62329694CLPTM1L, ORinteraction = 0.73, p = 2.70 × 10−13). Notably, even with much genetic heterogeneity across ethnicities, three pairs of SNPs in the 6p21.32 region identified from the European-ancestry population remained significant among an Asian population from the Nanjing Medical University Global Screening Array project (rs521828C6orf10 and rs204999PRRT1, ORinteraction = 1.13, p = 0.008; rs3135369BTNL2 and rs2858859HLA-DQA1, ORinteraction = 1.11, p = 5.23 × 10−4; rs3135369BTNL2 and rs9271300HLA-DQA1, ORinteraction = 0.89, p = 0.006). The interaction-empowered polygenetic risk score that integrated classical polygenetic risk score and G × G information score was remarkable in lung cancer risk stratification. ConclusionsImportant G × G interactions were identified and enriched in the 5p15.33 and 6p21.32 regions, which may enhance lung cancer screening models.

Reassessment of candidate gene studies for idiopathic restless legs syndrome in a large genome-wide association study dataset of European ancestry.

Several candidate gene studies have been published for idiopathic restless legs syndrome (RLS) in populations of European ancestry, but the reported associations have not been confirmed in independent samples. Our aim was to reassess these findings in a large case-control dataset in order to evaluate their validity. We screened PubMed for RLS candidate gene studies. We used the genome-wide association study (GWAS) dataset of the International EU-RLS-GENE Consortium as our replication sample, which provided genome-wide single-variant association data based on at most 17 220 individuals of European ancestry. We performed additional gene-based tests using the software MAGMA and assessed the power of our study using the genpwr R package. We identified 14 studies conducted in European samples which assessed 45 variants in 27 genes of which 5 variants had been reported as significantly associated. None of these individual variants were replicated in our GWAS-based reassessment (nominal p > 0.05) and gene-based tests for the respective five genes ADH1B, GABRR3, HMOX1, MAOA, and VDR, were also nonsignificant (nominal p > 0.05). Our replication dataset was well powered to detect the reported effects, even when adjusting for effect size overestimation due to winner's curse. Power estimates were close to 100% for all variants. In summary, none of the significant single-variant associations from candidate gene studies were confirmed in our GWAS dataset. Therefore, these associations were likely false positive. Our observations emphasize the need for large sample sizes and stringent significance thresholds in future association studies for RLS.

Using Mendelian randomisation to identify opportunities for type 2 diabetes prevention by repurposing medications used for lipid management.

SummaryBackgroundMaintaining a healthy lifestyle to reduce type 2 diabetes (T2D) risk is challenging and additional strategies for T2D prevention are needed. We evaluated several lipid control medications as potential therapeutic options for T2D prevention using tissue-specific predicted gene expression summary statistics in a two-sample Mendelian randomisation (MR) design.MethodsLarge-scale European genome-wide summary statistics for lipids and T2D were leveraged in our multi-stage analysis to estimate changes in either lipid levels or T2D risk driven by tissue-specific predicted gene expression. We incorporated tissue-specific predicted gene expression summary statistics to proxy therapeutic effects of three lipid control medications [i.e., statins, icosapent ethyl (IPE), and proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK-9i)] on T2D susceptibility using two-sample Mendelian randomisation (MR).FindingsIPE, as proxied via increased FADS1 expression, was predicted to lower triglycerides and was associated with a 53% reduced risk of T2D. Statins and PCSK-9i, as proxied by reduced HMGCR and PCSK9 expression, respectively, were predicted to lower LDL-C levels but were not associated with T2D susceptibility.InterpretationTriglyceride lowering via IPE may reduce the risk of developing T2D in populations of European ancestry. However, experimental validation using animal models is needed to substantiate our results and to motivate randomized control trials (RCTs) for IPE as putative treatment for T2D prevention.FundingOnly summary statistics were used in this analysis. Funding information is detailed under Acknowledgments.

The genetic architecture of Alzheimer disease risk in the Ohio and Indiana Amish.

SummaryAlzheimer disease (AD) is the most common type of dementia and is currently estimated to affect 6.2 million Americans. It ranks as the sixth leading cause of death in the United States, and the proportion of deaths due to AD has been increasing since 2000, while the proportion of many other leading causes of deaths have decreased or remained constant. The risk for AD is multifactorial, including genetic and environmental risk factors. Although APOE ε4 remains the largest genetic risk factor for AD, more than 26 other loci have been associated with AD risk. Here, we recruited Amish adults from Ohio and Indiana to investigate AD risk and protective genetic effects. As a founder population that typically practices endogamy, variants that are rare in the general population may be of a higher frequency in the Amish population. Since the Amish have a slightly lower incidence and later age of onset of disease, they represent an excellent and unique population for research on protective genetic variants. We compared AD risk in the Amish and to a non-Amish population through APOE genotype, a non-APOE genetic risk score of genome-wide significant variants, and a non-APOE polygenic risk score considering all of the variants. Our results highlight the lesser relative impact of APOE and differing genetic architecture of AD risk in the Amish compared to a non-Amish, general European ancestry population.

Evaluating breast cancer predisposition genes in women of African ancestry

PurposeStudies conducted primarily among European ancestry women reported 12 breast cancer predisposition genes. However, etiologic roles of these genes in breast cancer among African ancestry women have been less well-investigated. MethodsWe conducted a case-control study in African American women, which included 1117 breast cancer cases and 2169 cancer-free controls, and a pooled analysis, which included 7096 cases and 8040 controls of African descent. Odds ratios of associations with breast cancer risk were estimated. ResultsUsing sequence data, we identified 61 pathogenic variants in 12 breast cancer predisposition genes, including 11 pathogenic variants not yet reported in previous studies. Pooled analysis showed statistically significant associations of breast cancer risk with pathogenic variants in BRCA1, BRCA2, PALB2, ATM, CHEK2, TP53, NF1, RAD51C, and RAD51D (all P < .05). The associations with BRCA1, PALB2, and RAD51D were stronger for estrogen receptor (ER)-negative than for ER-positive breast cancer (P heterogeneity < .05), whereas the association with CHEK2 was stronger for ER-positive than for ER-negative breast cancer. ConclusionOur study confirmed previously identified associations of breast cancer risk with BRCA1, BRCA2, PALB2, ATM, TP53, NF1, and CHEK2 and provided new evidence to extend the associations of breast cancer risk with RAD51C and RAD51D, which was identified previously in European ancestry populations, to African ancestry women.

Genome-wide risk prediction of common diseases across ancestries in one million people

SummaryPolygenic risk scores (PRS) measure genetic disease susceptibility by combining risk effects across the genome. For coronary artery disease (CAD), type 2 diabetes (T2D), and breast and prostate cancer, we performed cross-ancestry evaluation of genome-wide PRSs in six biobanks in Europe, the United States, and Asia. We studied transferability of these highly polygenic, genome-wide PRSs across global ancestries, within European populations with different health-care systems, and local population substructures in a population isolate. All four PRSs had similar accuracy across European and Asian populations, with poorer transferability in the smaller group of individuals of African ancestry. The PRSs had highly similar effect sizes in different populations of European ancestry, and in early- and late-settlement regions with different recent population bottlenecks in Finland. Comparing genome-wide PRSs to PRSs containing a smaller number of variants, the highly polygenic, genome-wide PRSs generally displayed higher effect sizes and better transferability across global ancestries. Our findings indicate that in the populations investigated, the current genome-wide polygenic scores for common diseases have potential for clinical utility within different health-care settings for individuals of European ancestry, but that the utility in individuals of African ancestry is currently much lower.

Cross-ethnic analysis of common gene variants in hemostasis show lopsided representation of global populations in genetic databases

A majority of studies reporting human genetic variants were performed in populations of European ancestry whereas other global populations, and particularly many ethnolinguistic groups in other continents, are heavily underrepresented in these studies. To investigate the extent of this disproportionate representation of global populations concerning variants of significance to thrombosis and hemostasis, 845 single nucleotide polymorphisms (SNPs) in and around 34 genes associated with thrombosis and hemostasis and included in the commercial Axiom Precision Medicine Research Array (PMRA) were evaluated, using gene frequencies in 3 African (Somali and Luhya in East Africa, and Yoruba in West Africa) and 14 non-African (admixed American, East Asian, European, South Asian, and sub-groups) populations. Among the populations studied, Europeans were observed to be the best represented population by the hemostatic SNPs included in the PMRA. The European population also presented the largest number of common pharmacogenetic and pathogenic hemostatic variants reported in the ClinVar database. The number of such variants decreased the farther the genetic distance a population was from Europeans, with Yoruba and East Asians presenting the least number of clinically significant hemostatic SNPs in ClinVar while also being the two genetically most distinct populations from Europeans among the populations compared. Current study shows the lopsided representation of global populations as regards to hemostatic genetic variants listed in different commercial SNP arrays, such as the PMRA, and reported in genetic databases while also underlining the importance of inclusion of non-European ethnolinguistic populations in genomics studies designed to discover variants of significance to bleeding and thrombotic disorders.

Health influenced by genetics: A first comprehensive analysis of breast cancer high and moderate penetrance susceptibility genes in the Tunisian population.

Significant advances have been made to understand the genetic basis of breast cancer. High, moderate and low penetrance variants have been identified with inter-ethnic variability in mutation frequency and spectrum. Genome wide association studies (GWAS) are widely used to identify disease-associated SNPs. Understanding the functional impact of these risk-SNPs will help the translation of GWAS findings into clinical interventions. Here we aim to characterize the genetic patterns of high and moderate penetrance breast cancer susceptibility genes and to assess the functional impact of non-coding SNPs. We analyzed BRCA1/2, PTEN, STK11, TP53, ATM, BRIP1, CHEK2 and PALB2 genotype data obtained from 135 healthy participants genotyped using Affymetrix Genome-Wide Human SNP-Array 6.0. Haplotype analysis was performed using Haploview.V4.2 and PHASE.V2.1. Population structure and genetic differentiation were assessed using principal component analysis (PCA) and fixation index (FST). Functional annotation was performed using In Silico web-based tools including RegulomeDB and VARAdb. Haplotype analysis showed distinct LD patterns with high levels of recombination and haplotype blocks of moderate to small size. Our findings revealed also that the Tunisian population tends to have a mixed origin with European, South Asian and Mexican footprints. Functional annotation allowed the selection of 28 putative regulatory variants. Of special interest were BRCA1_ rs8176318 predicted to alter the binding sites of a tumor suppressor miRNA hsa-miR-149 and PALB2_ rs120963 located in tumorigenesis-associated enhancer and predicted to strongly affect the binding of P53. Significant differences in allele frequencies were observed with populations of African and European ancestries for rs8176318 and rs120963 respectively. Our findings will help to better understand the genetic basis of breast cancer by guiding upcoming genome wide studies in the Tunisian population. Putative functional SNPs may be used to develop an efficient polygenic risk score to predict breast cancer risk leading to better disease prevention and management.

Age Estimate of GJB2-p.(Arg143Trp) Founder Variant in Hearing Impairment in Ghana, Suggests Multiple Independent Origins across Populations.

Simple SummaryThe incidence of the GJB2-p.(Arg143Trp) founder mutation in numerous populations of different ethnolinguistic and geographical backgrounds has generated interest on the provenance and age of the variant, which is predominantly associated with non-syndromic hearing impairment in Ghana. To interrogate the multiple possible independent origins of the GJB2-p.(Arg143Trp) variant, we estimated the age of the variant in Ghana by Bayesian inference, using linked makers in whole-exome sequencing data from hearing-impaired unrelated individuals who are homozygous for the GJB2-p.(Arg143Trp) variant, and nonaffected controls from the same population. We estimated the age of the variant as approximately 9625 years, from a common indigenous Ghanaian ancestor. Haplotype backgrounds in Ghanaian hearing-impaired individuals were apparently different from those of their Japanese counterparts. We observed low haplotype diversity in the GJB2-p.(Arg143Trp) genomic region for homozygous individuals compared to the normal hearing Ghanaian controls, although the recombination rate is relatively high in the region. The GJB2-p.(Arg143Trp)-positive individuals shared no common haplotype with the Ghanaian GJB2-p.(Arg143Trp)-negative controls, and as well as no common haplotype with data extracted from populations in 1000 Genomes, further supporting the multiple independent origins of GJB2-p.(Arg143Trp) in the global population.Gap junction protein beta 2 (GJB2) (connexin 26) variants are commonly implicated in non-syndromic hearing impairment (NSHI). In Ghana, the GJB2 variant p.(Arg143Trp) is the largest contributor to NSHI and has a reported prevalence of 25.9% in affected multiplex families. To date, in the African continent, GJB2-p.(Arg143Trp) has only been reported in Ghana. Using whole-exome sequencing data from 32 individuals from 16 families segregating NSHI, and 38 unrelated hearing controls with the same ethnolinguistic background, we investigated the date and origin of p.(Arg143Trp) in Ghana using linked markers. With a Bayesian linkage disequilibrium gene mapping method, we estimated GJB2-p.(Arg143Trp) to have originated about 9625 years (385 generations) ago in Ghana. A haplotype analysis comparing data extracted from Ghanaians and those from the 1000 Genomes project revealed that GJB2-p.(Arg143Trp) is carried on different haplotype backgrounds in Ghanaian and Japanese populations, as well as among populations of European ancestry, lending further support to the multiple independent origins of the variant. In addition, we found substantial haplotype conservation in the genetic background of Ghanaian individuals with biallelic GJB2-p.(Arg143Trp) compared to the GJB2-p.(Arg143Trp)-negative group with normal hearing from Ghana, suggesting a strong evolutionary constraint in this genomic region in Ghanaian populations that are homozygous for GJB2-p.(Arg143Trp). The present study evaluates the age of GJB2-p.(Arg143Trp) at 9625 years and supports the multiple independent origins of this variant in the global population.