Displaying publications 1 - 20 of 188 in total

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  1. Yun Z, Shen Y, Yan X, Tian S, Wang J, Teo CS, et al.
    J Glob Health, 2024 Mar 15;14:04057.
    PMID: 38487860 DOI: 10.7189/jogh.14.04057
    BACKGROUND: Previous studies have yielded inconsistent results concerning drug use and the risk of cancers. We conducted a large-scale cross-sectional study and a two-sample Mendelian randomisation (MR) study to reveal the causal effect between the use of 19 medications and the risk of four common cancers (breast, lung, colorectal, and prostate).

    METHODS: We obtained information on medication use and cancer diagnosis from National Health and Nutrition Examination Survey participants. After propensity score matching, we conducted survey-weighted multivariate logistic regression and restricted cubic spline analysis to assess the observed correlation between medication use and cancer while adjusting for multiple covariates. We also performed MR analysis to investigate causality based on summary data from genome-wide association studies on medication use and cancers. We performed sensitivity analyses, replication analysis, genetic correlation analysis, and reverse MR analysis to improve the reliability of MR findings.

    RESULTS: We found that the use of agents acting on the renin-angiotensin system was associated with reduced risk of prostate cancer (odds ratio (OR) = 0.42; 95% confidence interval (CI) = 0.27-0.63, P 

    Matched MeSH terms: Genome-Wide Association Study*
  2. Lau NS, Furusawa G
    Sci Total Environ, 2024 Feb 20;912:169134.
    PMID: 38070563 DOI: 10.1016/j.scitotenv.2023.169134
    In this study, we present the genome characterization of a novel chitin-degrading strain, KSP-S5-2, and comparative genomics of 33 strains of Cellvibrionaceae. Strain KSP-S5-2 was isolated from mangrove sediment collected in Balik Pulau, Penang, Malaysia, and its 16S rRNA gene sequence showed the highest similarity (95.09%) to Teredinibacter franksiae. Genome-wide analyses including 16S rRNA gene sequence similarity, average nucleotide identity, digital DNA-DNA hybridization, and phylogenomics, suggested that KSP-S5-2 represents a novel species in the family Cellvibrionaceae. The Cellvibrionaceae pan-genome exhibited high genomic variability, with only 1.7% representing the core genome, while the flexible genome showed a notable enrichment of genes related to carbohydrate metabolism and transport pathway. This observation sheds light on the genetic plasticity of the Cellvibrionaceae family and the gene pools that form the basis for the evolution of polysaccharide-degrading capabilities. Comparative analysis of the carbohydrate-active enzymes across Cellvibrionaceae strains revealed that the chitinolytic system is not universally present within the family, as only 18 of the 33 genomes encoded chitinases. Strain KSP-S5-2 displayed an expanded repertoire of chitinolytic enzymes (25 GH18, two GH19 chitinases, and five GH20 β-N-acetylhexosaminidases) but lacked genes for agar, xylan, and pectin degradation, indicating specialized enzymatic machinery focused primarily on chitin degradation. Further, the strain degraded 90% of chitin after 10 days of incubation. In summary, our findings provided insights into strain KSP-S5-2's genomic potential, the genetics of its chitinolytic system, genomic diversity within the Cellvibrionaceae family in terms of polysaccharide degradation, and its application for chitin degradation.
    Matched MeSH terms: Genome-Wide Association Study
  3. Wang A, Shen J, Rodriguez AA, Saunders EJ, Chen F, Janivara R, et al.
    Nat Genet, 2023 Dec;55(12):2065-2074.
    PMID: 37945903 DOI: 10.1038/s41588-023-01534-4
    The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.
    Matched MeSH terms: Genome-Wide Association Study
  4. Ghazali N, Rahman NA, Kannan TP, Ahmad A, Sulong S
    BMC Oral Health, 2023 Nov 29;23(1):945.
    PMID: 38031027 DOI: 10.1186/s12903-023-03464-3
    BACKGROUND: Nonsyndromic cleft lip and/or without cleft palate (NSCL/P) with or without hypodontia is a common developmental aberration in humans and animals. This study aimed to identify the loss of heterozygosity (LOH) involved in hypodontia and NSCL/P pathogenesis.

    METHODS: This is a cross-sectional study that conducted genome-wide copy number analysis using CytoScan 750K array on salivary samples from Malay subjects with NSCL/P with or without hypodontia aged 7-13 years. To confirm the significant results, simple logistic regression was employed to conduct statistical data analysis using SPSS software.

    RESULTS: The results indicated the most common recurrent copy neutral LOH (cnLOH) observed at 1p33-1p32.3, 1q32.2-1q42.13 and 6p12.1-6p11.1 loci in 8 (13%), 4 (7%), and 3 (5%) of the NSCL/P subjects, respectively. The cnLOHs at 1p33-1p32.3 (D1S197), 1q32.2-1q42.13 (D1S160), and 6p12.1-6p11.1 (D1S1661) were identified observed in NSCL/P and noncleft children using microsatellite analysis markers as a validation analysis. The regions affected by the cnLOHs at 1p33-1p32.3, 1q32.2-1q42.13, and 6p12.1-6p11.1 loci contained selected genes, namely FAF1, WNT3A and BMP5, respectively. There was a significant association between the D1S197 (1p33-32.3) markers containing the FAF1 gene among NSCL/P subjects with or without hypodontia compared with the noncleft subjects (p-value = 0.023).

    CONCLUSION: The results supported the finding that the genetic aberration on 1p33-32.3 significantly contributed to the development of NSCL/P with or without hypodontia. These results have an exciting prospect in the promising field of individualized preventive oral health care.

    Matched MeSH terms: Genome-Wide Association Study
  5. Chen Z, Song J, Tang L
    BMC Oral Health, 2023 Nov 02;23(1):827.
    PMID: 37919698 DOI: 10.1186/s12903-023-03575-x
    OBJECTIVE: Several research has considered the potential correlation between periodontitis and serum lipids. However, serum lipid profiles correlation with periodontitis remains largely unknown. The investigation objective was to examine periodontitis correlation with serum lipid levels using a bidirectional Mendelian randomization (MR) analysis.

    METHODS: The study employed a bidirectional MR analysis with two samples, utilizing a freely accessible genome-wide association study (GWAS). Furthermore, the primary analysis employed the inverse variance weighted (IVW) method. To determine whether the lipid profiles were associated with periodontitis, a variety of sensitivity analyses (including MR-Egger regression, MR-PRESSO, and weighted median), as well as multivariable MR, were employed.

    RESULTS: MR analysis performed by IVW did not reveal any relationship between periodontitis and low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TG), or total cholesterol (TC). It was also found that LDL, HDL, TG, and TC were not associated to periodontitis. Furthermore, the MR estimations exhibited consistency with other MR sensitivity and multivariate MR (MVMR) analyses. These results show that the correlation between serum lipid levels and periodontitis could not be established.

    CONCLUSION: The finding indicates a negligible link between periodontitis and serum lipid levels were identified, despite previous observational studies reporting a link between periodontitis and serum lipid levels.

    Matched MeSH terms: Genome-Wide Association Study*
  6. Zhang Y, Liu S, De Meyer M, Liao Z, Zhao Y, Virgilio M, et al.
    J Adv Res, 2023 Nov;53:61-74.
    PMID: 36574947 DOI: 10.1016/j.jare.2022.12.012
    INTRODUCTION: The oriental fruit fly Bactrocera dorsalis is one of the most destructive agricultural pests worldwide, with highly debated species delimitation, origin, and global spread routes.

    OBJECTIVES: Our study intended to (i) resolve the taxonomic uncertainties between B. dorsalis and B. carambolae, (ii) reveal the population structure and global invasion routes of B. dorsalis across Asia, Africa, and Oceania, and (iii) identify genomic regions that are responsible for the thermal adaptation of B. dorsalis.

    METHODS: Based on a high-quality chromosome-level reference genome assembly, we explored the population relationship using a genome-scale single nucleotide polymorphism dataset generated from the resequencing data of 487 B. dorsalis genomes and 25 B. carambolae genomes. Genome-wide association studies and silencing using RNA interference were used to identify and verify the candidate genes associated with extreme thermal stress.

    RESULTS: We showed that B. dorsalis originates from the Southern India region with three independent invasion and spread routes worldwide: (i) from Northern India to Northern Southeast Asia, then to Southern Southeast Asia; (ii) from Northern India to Northern Southeast Asian, then to China and Hawaii; and (iii) from Southern India toward the African mainland, then to Madagascar, which is mainly facilitated by human activities including trade and immigration. Twenty-seven genes were identified by a genome-wide association study to be associated with 11 temperature bioclimatic variables. The Cyp6a9 gene may enhance the thermal adaptation of B. dorsalis and thus boost its invasion, which tended to be upregulated at a hardening temperature of 38 °C. Functional verification using RNA interference silencing against Cyp6a9, led to the specific decrease in Cyp6a9 expression, reducing the survival rate of dsRNA-feeding larvae exposed to extreme thermal stress of 45 °C after heat hardening treatments in B. dorsalis.

    CONCLUSION: This study provides insights into the evolutionary history and genetic basis of temperature adaptation in B. dorsalis.

    Matched MeSH terms: Genome-Wide Association Study
  7. Mariapun S, Ho WK, Eriksson M, Tai MC, Mohd Taib NA, Yip CH, et al.
    Breast Cancer Res Treat, 2023 Sep;201(2):237-245.
    PMID: 37338730 DOI: 10.1007/s10549-023-06984-2
    PURPOSE: Mammographic density (MD), after accounting for age and body mass index (BMI), is a strong heritable risk factor for breast cancer. Genome-wide association studies (GWAS) have identified 64 SNPs in 55 independent loci associated with MD in women of European ancestry. Their associations with MD in Asian women, however, are largely unknown.

    METHOD: Using linear regression adjusting for age, BMI, and ancestry-informative principal components, we evaluated the associations of previously reported MD-associated SNPs with MD in a multi-ethnic cohort of Asian ancestry. Area and volumetric mammographic densities were determined using STRATUS (N = 2450) and Volpara™ (N = 2257). We also assessed the associations of these SNPs with breast cancer risk in an Asian population of 14,570 cases and 80,870 controls.

    RESULTS: Of the 61 SNPs available in our data, 21 were associated with MD at a nominal threshold of P value  0.05, 29 variants showed consistent directions of association as those previously reported. We found that nine of the 21 MD-associated SNPs in this study were also associated with breast cancer risk in Asian women (P 

    Matched MeSH terms: Genome-Wide Association Study
  8. Wang X, Walker A, Revez JA, Ni G, Adams MJ, McIntosh AM, et al.
    Am J Hum Genet, 2023 Jul 06;110(7):1207-1215.
    PMID: 37379836 DOI: 10.1016/j.ajhg.2023.06.006
    In polygenic score (PGS) analysis, the coefficient of determination (R2) is a key statistic to evaluate efficacy. R2 is the proportion of phenotypic variance explained by the PGS, calculated in a cohort that is independent of the genome-wide association study (GWAS) that provided estimates of allelic effect sizes. The SNP-based heritability (hSNP2, the proportion of total phenotypic variances attributable to all common SNPs) is the theoretical upper limit of the out-of-sample prediction R2. However, in real data analyses R2 has been reported to exceed hSNP2, which occurs in parallel with the observation that hSNP2 estimates tend to decline as the number of cohorts being meta-analyzed increases. Here, we quantify why and when these observations are expected. Using theory and simulation, we show that if heterogeneities in cohort-specific hSNP2 exist, or if genetic correlations between cohorts are less than one, hSNP2 estimates can decrease as the number of cohorts being meta-analyzed increases. We derive conditions when the out-of-sample prediction R2 will be greater than hSNP2 and show the validity of our derivations with real data from a binary trait (major depression) and a continuous trait (educational attainment). Our research calls for a better approach to integrating information from multiple cohorts to address issues of between-cohort heterogeneity.
    Matched MeSH terms: Genome-Wide Association Study*
  9. Darst BF, Shen J, Madduri RK, Rodriguez AA, Xiao Y, Sheng X, et al.
    Am J Hum Genet, 2023 Jul 06;110(7):1200-1206.
    PMID: 37311464 DOI: 10.1016/j.ajhg.2023.05.010
    Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS269). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI = 0.635-0.677) in African and 0.844 (95% CI = 0.840-0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95% CI = 1.67-2.00) and 2.19 (95% CI = 2.14-2.25), respectively, for each SD unit increase in the GW-PRS. Compared to the GW-PRS, in African and European ancestry men, the PRS269 had larger or similar AUCs (AUC = 0.679, 95% CI = 0.659-0.700 and AUC = 0.845, 95% CI = 0.841-0.849, respectively) and comparable prostate cancer ORs (OR = 2.05, 95% CI = 1.87-2.26 and OR = 2.21, 95% CI = 2.16-2.26, respectively). Findings were similar in the validation studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS269 developed from multi-ancestry GWASs and fine-mapping.
    Matched MeSH terms: Genome-Wide Association Study
  10. Jee YH, Ho WK, Park S, Easton DF, Teo SH, Jung KJ, et al.
    Int J Epidemiol, 2023 Jun 06;52(3):796-805.
    PMID: 36343017 DOI: 10.1093/ije/dyac206
    BACKGROUND: Polygenic risk scores (PRSs) for breast cancer, developed using European and Asian genome-wide association studies (GWAS), have been shown to have good discrimination in Asian women. However, prospective calibration of absolute risk prediction models, based on a PRS or PRS combined with lifestyle, clinical and environmental factors, in Asian women is limited.

    METHODS: We consider several PRSs trained using European and/or Asian GWAS. For each PRS, we evaluate the discrimination and calibration of three absolute risk models among 41 031 women from the Korean Cancer Prevention Study (KCPS)-II Biobank: (i) a model using incidence, mortality and risk factor distributions (reference inputs) among US 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 discrimination over lifestyle, clinical and environmental (Qx) factors in Korean women. US-based absolute risk models overestimated the risks for women aged ≥50 years, and this overestimation was larger for models that only included PRS (expected-to-observed ratio E/O = 1.2 for women <50, E/O = 2.7 for women ≥50). Recalibrated and Korean-based risk models had better calibration in the large, although the risk in the highest decile was consistently overestimated. Absolute risk projections suggest that risk-reducing lifestyle changes would lead to larger absolute risk reductions among women at higher PRS.

    CONCLUSIONS: Absolute risk models incorporating PRS trained in European and Asian GWAS and population-appropriate average age-specific incidences may be useful for risk-stratified interventions in Korean women.

    Matched MeSH terms: Genome-Wide Association Study
  11. Zakaria WNA, Sasongko TH, Al-Rahbi B, Al-Sowayan N, Ahmad AH, Zakaria R, et al.
    Psychiatr Genet, 2023 Apr 01;33(2):37-49.
    PMID: 36825838 DOI: 10.1097/YPG.0000000000000336
    This study aimed to perform a bibliometric analysis on genetic studies in schizophrenia in the pregenome-wide association studies (GWAS) and post-GWAS era. We searched the literature on genes and schizophrenia using the Scopus database. The documents increased with time, especially after the human genome project and International HapMap Project, with the highest citation in 2008. The top occurrence author keywords were discovered to be different in the pre-GWAS and post-GWAS eras, reflecting the progress of genetic studies connected to schizophrenia. Emerging keywords highlighted a trend towards an application of precision medicine, showing an interplay of environmental exposures as well as genetic factors in schizophrenia pathogenesis, progression, and response to therapy. In conclusion, the gene and schizophrenia literature has grown rapidly after the human genome project, and the temporal variation in the author keywords pattern reflects the trend of genetic studies related to schizophrenia in the pre-GWAS and post-GWAS era.
    Matched MeSH terms: Genome-Wide Association Study*
  12. Mueller SH, Lai AG, Valkovskaya M, Michailidou K, Bolla MK, Wang Q, et al.
    Genome Med, 2023 Jan 26;15(1):7.
    PMID: 36703164 DOI: 10.1186/s13073-022-01152-5
    BACKGROUND: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes.

    METHODS: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry.

    RESULTS: In European ancestry samples, 14 genes were significantly associated (q 

    Matched MeSH terms: Genome-Wide Association Study/methods
  13. Jia G, Ping J, Shu X, Yang Y, Cai Q, Kweon SS, et al.
    Am J Hum Genet, 2022 Dec 01;109(12):2185-2195.
    PMID: 36356581 DOI: 10.1016/j.ajhg.2022.10.011
    By combining data from 160,500 individuals with breast cancer and 226,196 controls of Asian and European ancestry, we conducted genome- and transcriptome-wide association studies of breast cancer. We identified 222 genetic risk loci and 137 genes that were associated with breast cancer risk at a p 
    Matched MeSH terms: Genome-Wide Association Study*
  14. Mostofa F, Yasid NA, Shamsi S, Ahmad SA, Mohd-Yusoff NF, Abas F, et al.
    Molecules, 2022 Nov 28;27(23).
    PMID: 36500396 DOI: 10.3390/molecules27238304
    The bone morphogenic protein (BMP) family is a member of the TGF-beta superfamily and plays a crucial role during the onset of gut inflammation and arthritis diseases. Recent studies have reported a connection with the gut-joint axis; however, the genetic players are still less explored. Meanwhile, BDMC33 is a newly synthesized anti-inflammatory drug candidate. Therefore, in our present study, we analysed the genome-wide features of the BMP family as well as the role of BMP members in gut-associated arthritis in an inflammatory state and the ability of BDMC33 to attenuate this inflammation. Firstly, genome-wide analyses were performed on the BMP family in the zebrafish genome, employing several in silico techniques. Afterwards, the effects of curcumin analogues on BMP gene expression in zebrafish larvae induced with TNBS (0.78 mg/mL) were determined using real time-qPCR. A total of 38 identified BMP proteins were revealed to be clustered in five major clades and contain TGF beta and TGF beta pro peptide domains. Furthermore, BDMC33 suppressed the expression of four selected BMP genes in the TNBS-induced larvae, where the highest gene suppression was in the BMP2a gene (an eight-fold decrement), followed by BMP7b (four-fold decrement), BMP4 (four-fold decrement), and BMP6 (three-fold decrement). Therefore, this study reveals the role of BMPs in gut-associated arthritis and proves the ability of BDMC33 to act as a potential anti-inflammatory drug for suppressing TNBS-induced BMP genes in zebrafish larvae.
    Matched MeSH terms: Genome-Wide Association Study
  15. Ishigaki K, Sakaue S, Terao C, Luo Y, Sonehara K, Yamaguchi K, et al.
    Nat Genet, 2022 Nov;54(11):1640-1651.
    PMID: 36333501 DOI: 10.1038/s41588-022-01213-w
    Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P 
    Matched MeSH terms: Genome-Wide Association Study*
  16. Schumacher-Schuh AF, Bieger A, Okunoye O, Mok KY, Lim SY, Bardien S, et al.
    Mov Disord, 2022 Aug;37(8):1593-1604.
    PMID: 35867623 DOI: 10.1002/mds.29126
    BACKGROUND: Human genetics research lacks diversity; over 80% of genome-wide association studies have been conducted on individuals of European ancestry. In addition to limiting insights regarding disease mechanisms, disproportionate representation can create disparities preventing equitable implementation of personalized medicine.

    OBJECTIVE: This systematic review provides an overview of research involving Parkinson's disease (PD) genetics in underrepresented populations (URP) and sets a baseline to measure the future impact of current efforts in those populations.

    METHODS: We searched PubMed and EMBASE until October 2021 using search strings for "PD," "genetics," the main "URP," and and the countries in Latin America, Caribbean, Africa, Asia, and Oceania (excluding Australia and New Zealand). Inclusion criteria were original studies, written in English, reporting genetic results on PD from non-European populations. Two levels of independent reviewers identified and extracted information.

    RESULTS: We observed imbalances in PD genetic studies among URPs. Asian participants from Greater China were described in the majority of the articles published (57%), but other populations were less well studied; for example, Blacks were represented in just 4.0% of the publications. Also, although idiopathic PD was more studied than monogenic forms of the disease, most studies analyzed a limited number of genetic variants. We identified just nine studies using a genome-wide approach published up to 2021, including URPs.

    CONCLUSION: This review provides insight into the significant lack of population diversity in PD research highlighting the immediate need for better representation. The Global Parkinson's Genetics Program (GP2) and similar initiatives aim to impact research in URPs, and the early metrics presented here can be used to measure progress in the field of PD genetics in the future. © 2022 International Parkinson and Movement Disorder Society.

    Matched MeSH terms: Genome-Wide Association Study
  17. Morales Berstein F, McCartney DL, Lu AT, Tsilidis KK, Bouras E, Haycock P, et al.
    Elife, 2022 Mar 29;11.
    PMID: 35346416 DOI: 10.7554/eLife.75374
    BACKGROUND: Epigenetic clocks have been associated with cancer risk in several observational studies. Nevertheless, it is unclear whether they play a causal role in cancer risk or if they act as a non-causal biomarker.

    METHODS: We conducted a two-sample Mendelian randomization (MR) study to examine the genetically predicted effects of epigenetic age acceleration as measured by HannumAge (nine single-nucleotide polymorphisms (SNPs)), Horvath Intrinsic Age (24 SNPs), PhenoAge (11 SNPs), and GrimAge (4 SNPs) on multiple cancers (i.e. breast, prostate, colorectal, ovarian and lung cancer). We obtained genome-wide association data for biological ageing from a meta-analysis (N = 34,710), and for cancer from the UK Biobank (N cases = 2671-13,879; N controls = 173,493-372,016), FinnGen (N cases = 719-8401; N controls = 74,685-174,006) and several international cancer genetic consortia (N cases = 11,348-122,977; N controls = 15,861-105,974). Main analyses were performed using multiplicative random effects inverse variance weighted (IVW) MR. Individual study estimates were pooled using fixed effect meta-analysis. Sensitivity analyses included MR-Egger, weighted median, weighted mode and Causal Analysis using Summary Effect Estimates (CAUSE) methods, which are robust to some of the assumptions of the IVW approach.

    RESULTS: Meta-analysed IVW MR findings suggested that higher GrimAge acceleration increased the risk of colorectal cancer (OR = 1.12 per year increase in GrimAge acceleration, 95% CI 1.04-1.20, p = 0.002). The direction of the genetically predicted effects was consistent across main and sensitivity MR analyses. Among subtypes, the genetically predicted effect of GrimAge acceleration was greater for colon cancer (IVW OR = 1.15, 95% CI 1.09-1.21, p = 0.006), than rectal cancer (IVW OR = 1.05, 95% CI 0.97-1.13, p = 0.24). Results were less consistent for associations between other epigenetic clocks and cancers.

    CONCLUSIONS: GrimAge acceleration may increase the risk of colorectal cancer. Findings for other clocks and cancers were inconsistent. Further work is required to investigate the potential mechanisms underlying the results.

    FUNDING: FMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z which is part of grant 218495/Z/19/Z). KKT was supported by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme) and by the Hellenic Republic's Operational Programme 'Competitiveness, Entrepreneurship & Innovation' (OΠΣ 5047228). PH was supported by Cancer Research UK (C18281/A29019). RMM was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). RMM is a National Institute for Health Research Senior Investigator (NIHR202411). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and CLR were supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/5, respectively) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). REM was supported by an Alzheimer's Society project grant (AS-PG-19b-010) and NIH grant (U01 AG-18-018, PI: Steve Horvath). RCR is a de Pass Vice Chancellor's Research Fellow at the University of Bristol.

    Matched MeSH terms: Genome-Wide Association Study/methods
  18. Ho WK, Tai MC, Dennis J, Shu X, Li J, Ho PJ, et al.
    Genet Med, 2022 Mar;24(3):586-600.
    PMID: 34906514 DOI: 10.1016/j.gim.2021.11.008
    PURPOSE: Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups.

    METHODS: The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases).

    RESULTS: The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk.

    CONCLUSION: PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry.

    Matched MeSH terms: Genome-Wide Association Study
  19. Mullins N, Kang J, Campos AI, Coleman JRI, Edwards AC, Galfalvy H, et al.
    Biol Psychiatry, 2022 Feb 01;91(3):313-327.
    PMID: 34861974 DOI: 10.1016/j.biopsych.2021.05.029
    BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.

    METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.

    RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.

    CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

    Matched MeSH terms: Genome-Wide Association Study
  20. Singh B, Maiti GP, Zhou X, Fazel-Najafabadi M, Bae SC, Sun C, et al.
    Arthritis Rheumatol, 2021 Dec;73(12):2303-2313.
    PMID: 33982894 DOI: 10.1002/art.41799
    OBJECTIVE: In a recent genome-wide association study, a significant genetic association between rs34330 of CDKN1B and risk of systemic lupus erythematosus (SLE) in Han Chinese was identified. This study was undertaken to validate the reported association and elucidate the biochemical mechanisms underlying the effect of the variant.

    METHODS: We performed an allelic association analysis in patients with SLE, followed by a meta-analysis assessing genome-wide association data across 11 independent cohorts (n = 28,872). In silico bioinformatics analysis and experimental validation in SLE-relevant cell lines were applied to determine the functional consequences of rs34330.

    RESULTS: We replicated a genetic association between SLE and rs34330 (meta-analysis P = 5.29 × 10-22 , odds ratio 0.84 [95% confidence interval 0.81-0.87]). Follow-up bioinformatics and expression quantitative trait locus analysis suggested that rs34330 is located in active chromatin and potentially regulates several target genes. Using luciferase and chromatin immunoprecipitation-real-time quantitative polymerase chain reaction, we demonstrated substantial allele-specific promoter and enhancer activity, and allele-specific binding of 3 histone marks (H3K27ac, H3K4me3, and H3K4me1), RNA polymerase II (Pol II), CCCTC-binding factor, and a critical immune transcription factor (interferon regulatory factor 1 [IRF-1]). Chromosome conformation capture revealed long-range chromatin interactions between rs34330 and the promoters of neighboring genes APOLD1 and DDX47, and effects on CDKN1B and the other target genes were directly validated by clustered regularly interspaced short palindromic repeat (CRISPR)-based genome editing. Finally, CRISPR/dead CRISPR-associated protein 9-based epigenetic activation/silencing confirmed these results. Gene-edited cell lines also showed higher levels of proliferation and apoptosis.

    CONCLUSION: Collectively, these findings suggest a mechanism whereby the rs34330 risk allele (C) influences the presence of histone marks, RNA Pol II, and IRF-1 transcription factor to regulate expression of several target genes linked to proliferation and apoptosis. This process could potentially underlie the association of rs34330 with SLE.

    Matched MeSH terms: Genome-Wide Association Study
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