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Fulltext Genome-wide association studies identify susceptibility loci for epithelial ovarian cancer in east Asian women

Lawrenson K, Song F, Hazelett DJ, Kar SP, Tyrer J, Phelan CM, et al.

Gynecol Oncol, 2019 05;153(2):343-355.
PMID: 30898391 DOI: 10.1016/j.ygyno.2019.02.023

OBJECTIVE: Genome-wide association studies (GWASs) for epithelial ovarian cancer (EOC) have focused largely on populations of European ancestry. We aimed to identify common germline variants associated with EOC risk in Asian women.
METHODS: Genotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations.
RESULTS: At chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR] = 1.34, P = 8.7 × 10-9) and high-grade serous EOC (HGSOC) (OR = 1.34, P = 4.3 × 10-9). SNP rs6902488 at 6p25.2 (r2 = 0.97 with rs7748275) lies in an active enhancer and is predicted to impact binding of STAT3, P300 and ELF1. We identified additional risk loci with low Bayesian false discovery probability (BFDP) scores, indicating they are likely to be true risk associations (BFDP <10%). At chromosome 20q11.22, rs74272064 was associated with HGSOC risk (OR = 1.27, P = 9.0 × 10-8). Overall EOC risk was associated with rs10260419 at chromosome 7p21.3 (OR = 1.33, P = 1.2 × 10-7) and rs74917072 at chromosome 2q37.3 (OR = 1.25, P = 4.7 × 10-7). At 2q37.3, expression quantitative trait locus analysis in 404 HGSOC tissues identified ESPNL as a putative candidate susceptibility gene (P = 1.2 × 10-7).
CONCLUSION: While some risk loci were shared between East Asian and European populations, others were population-specific, indicating that the landscape of EOC risk in Asian women has both shared and unique features compared to women of European ancestry.

Matched MeSH terms: Genome-Wide Association Study
Fulltext Singapore Genome Variation Project: a haplotype map of three Southeast Asian populations

Teo YY, Sim X, Ong RT, Tan AK, Chen J, Tantoso E, et al.

Genome Res, 2009 Nov;19(11):2154-62.
PMID: 19700652 DOI: 10.1101/gr.095000.109

The Singapore Genome Variation Project (SGVP) provides a publicly available resource of 1.6 million single nucleotide polymorphisms (SNPs) genotyped in 268 individuals from the Chinese, Malay, and Indian population groups in Southeast Asia. This online database catalogs information and summaries on genotype and phased haplotype data, including allele frequencies, assessment of linkage disequilibrium (LD), and recombination rates in a format similar to the International HapMap Project. Here, we introduce this resource and describe the analysis of human genomic variation upon agglomerating data from the HapMap and the Human Genome Diversity Project, providing useful insights into the population structure of the three major population groups in Asia. In addition, this resource also surveyed across the genome for variation in regional patterns of LD between the HapMap and SGVP populations, and for signatures of positive natural selection using two well-established metrics: iHS and XP-EHH. The raw and processed genetic data, together with all population genetic summaries, are publicly available for download and browsing through a web browser modeled with the Generic Genome Browser.

Matched MeSH terms: Genome-Wide Association Study/methods
Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry

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
Fulltext Discerning the Origins of the Negritos, First Sundaland People: Deep Divergence and Archaic Admixture

Jinam TA, Phipps ME, Aghakhanian F, Majumder PP, Datar F, Stoneking M, et al.

Genome Biol Evol, 2017 08 01;9(8):2013-2022.
PMID: 28854687 DOI: 10.1093/gbe/evx118

Human presence in Southeast Asia dates back to at least 40,000 years ago, when the current islands formed a continental shelf called Sundaland. In the Philippine Islands, Peninsular Malaysia, and Andaman Islands, there exist indigenous groups collectively called Negritos whose ancestry can be traced to the "First Sundaland People." To understand the relationship between these Negrito groups and their demographic histories, we generated genome-wide single nucleotide polymorphism data in the Philippine Negritos and compared them with existing data from other populations. Phylogenetic tree analyses show that Negritos are basal to other East and Southeast Asians, and that they diverged from West Eurasians at least 38,000 years ago. We also found relatively high traces of Denisovan admixture in the Philippine Negritos, but not in the Malaysian and Andamanese groups, suggesting independent introgression and/or parallel losses involving Denisovan introgressed regions. Shared genetic loci between all three Negrito groups could be related to skin pigmentation, height, facial morphology and malarial resistance. These results show the unique status of Negrito groups as descended from the First Sundaland People.

Matched MeSH terms: Genome-Wide Association Study
Fulltext Polygenic risk scores for prediction of breast cancer risk in Asian populations

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
Fulltext Genetic associations of the INSIG2 rs7566605 polymorphism with obesity-related metabolic traits in Malaysian Malays

Apalasamy YD, Moy FM, Rampal S, Bulgiba A, Mohamed Z

Genet. Mol. Res., 2014;13(3):4904-10.
PMID: 25062423 DOI: 10.4238/2014.July.4.4

A genome-wide association study showed that the tagging single nucleotide polymorphism (SNP) rs7566605 in the insulin-induced gene 2 (INSIG2) was associated with obesity. Attempts to replicate this result in different populations have produced inconsistent findings. We aimed to study the association between the rs7566605 SNP with obesity and other metabolic parameters in Malaysian Malays. Anthropometric and obesity-related metabolic parameters and DNA samples were collected. We genotyped the rs7566605 polymorphism in 672 subjects using real-time polymerase chain reaction. No significant associations were found between the rs7566605 tagging SNP of INSIG2 with obesity or other metabolic parameters in the Malaysian Malay population. The INSIG2 rs7566605 SNP may not play a role in the development of obesity-related metabolic traits in Malaysian Malays.

Matched MeSH terms: Genome-Wide Association Study
Contributions of IKZF1, DDC, CDKN2A, CEBPE, and LMO1 Gene Polymorphisms to Acute Lymphoblastic Leukemia in a Yemeni Population

Al-Absi B, Razif MFM, Noor SM, Saif-Ali R, Aqlan M, Salem SD, et al.

Genet Test Mol Biomarkers, 2017 Oct;21(10):592-599.
PMID: 28768142 DOI: 10.1089/gtmb.2017.0084

BACKGROUND: Genome-wide and candidate gene association studies have previously revealed links between a predisposition to acute lymphoblastic leukemia (ALL) and genetic polymorphisms in the following genes: IKZF1 (7p12.2; ID: 10320), DDC (7p12.2; ID: 1644), CDKN2A (9p21.3; ID: 1029), CEBPE (14q11.2; ID: 1053), and LMO1 (11p15; ID: 4004). In this study, we aimed to conduct an investigation into the possible association between polymorphisms in these genes and ALL within a sample of Yemeni children of Arab-Asian descent.
METHODS: Seven single-nucleotide polymorphisms (SNPs) in IKZF1, three SNPs in DDC, two SNPs in CDKN2A, two SNPs in CEBPE, and three SNPs in LMO1 were genotyped in 289 Yemeni children (136 cases and 153 controls), using the nanofluidic Dynamic Array (Fluidigm 192.24 Dynamic Array). Logistic regression analyses were used to estimate ALL risk, and the strength of association was expressed as odds ratios with 95% confidence intervals.
RESULTS: We found that the IKZF1 SNP rs10235796 C allele (p = 0.002), the IKZF1 rs6964969 A>G polymorphism (p = 0.048, GG vs. AA), the CDKN2A rs3731246 G>C polymorphism (p = 0.047, GC+CC vs. GG), and the CDKN2A SNP rs3731246 C allele (p = 0.007) were significantly associated with ALL in Yemenis of Arab-Asian descent. In addition, a borderline association was found between IKZF1 rs4132601 T>G variant and ALL risk. No associations were found between the IKZF1 SNPs (rs11978267; rs7789635), DDC SNPs (rs3779084; rs880028; rs7809758), CDKN2A SNP (rs3731217), the CEBPE SNPs (rs2239633; rs12434881) and LMO1 SNPs (rs442264; rs3794012; rs4237770) with ALL in Yemeni children.
CONCLUSION: The IKZF1 SNPs, rs10235796 and rs6964969, and the CDKN2A SNP rs3731246 (previously unreported) could serve as risk markers for ALL susceptibility in Yemeni children.

Matched MeSH terms: Genome-Wide Association Study/methods
Inference of the Genetic Polymorphisms of CYP2D6 in Six Subtribes of the Malaysian Orang Asli from Whole-Genome Sequencing Data

Yu CY, Ang GY, Subramaniam V, Johari James R, Ahmad A, Abdul Rahman T, et al.

Genet Test Mol Biomarkers, 2017 Jul;21(7):409-415.
PMID: 28525288 DOI: 10.1089/gtmb.2016.0235

AIMS: CYP2D6 is one of the major enzymes in the cytochrome P450 monooxygenase system. It metabolizes ∼25% of prescribed drugs and hence, the genetic diversity of a CYP2D6 gene has continued to be of great interest to the medical and pharmaceutical industries. This study was designed to perform a systematic analysis of the CYP2D6 gene in six subtribes of the Malaysian Orang Asli.
METHODS: Genomic DNAs were extracted from the blood samples followed by whole-genome sequencing. The reads were aligned to the reference human genome hg19 and variants in the CYP2D6 gene were analyzed. CYP2D6*5 and duplication of CYP2D6 were analyzed using previously established methods.
RESULTS: A total of 72 single nucleotide polymorphisms were identified. CYP2D6*1, *2, *4, *5, *10,*41, and duplication of the gene were found in the Orang Asli, whereby CYP2D6*2 and *41 alleles are reported for the first time in the Malaysian population.
CONCLUSION: The findings in this study provide insights into the genetic polymorphisms of CYP2D6 in the Orang Asli of Peninsular Malaysia.

Matched MeSH terms: Genome-Wide Association Study/methods
Fulltext Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk

Amankwah EK, Lin HY, Tyrer JP, Lawrenson K, Dennis J, Chornokur G, et al.

Genet Epidemiol, 2015 Dec;39(8):689-97.
PMID: 26399219 DOI: 10.1002/gepi.21921

Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value <0.05 and a false discovery rate (FDR) <0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07-1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27-2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69-0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.

Matched MeSH terms: Genome-Wide Association Study
The utility of the Laplace effect size prior distribution in Bayesian fine-mapping studies

Walters K, Cox A, Yaacob H

Genet Epidemiol, 2021 Jun;45(4):386-401.
PMID: 33410201 DOI: 10.1002/gepi.22375

The Gaussian distribution is usually the default causal single-nucleotide polymorphism (SNP) effect size prior in Bayesian population-based fine-mapping association studies, but a recent study showed that the heavier-tailed Laplace prior distribution provided a better fit to breast cancer top hits identified in genome-wide association studies. We investigate the utility of the Laplace prior as an effect size prior in univariate fine-mapping studies. We consider ranking SNPs using Bayes factors and other summaries of the effect size posterior distribution, the effect of prior choice on credible set size based on the posterior probability of causality, and on the noteworthiness of SNPs in univariate analyses. Across a wide range of fine-mapping scenarios the Laplace prior generally leads to larger 90% credible sets than the Gaussian prior. These larger credible sets for the Laplace prior are due to relatively high prior mass around zero which can yield many noncausal SNPs with relatively large Bayes factors. If using conventional credible sets, the Gaussian prior generally yields a better trade off between including the causal SNP with high probability and keeping the set size reasonable. Interestingly when using the less well utilised measure of noteworthiness, the Laplace prior performs well, leading to causal SNPs being declared noteworthy with high probability, whilst generally declaring fewer than 5% of noncausal SNPs as being noteworthy. In contrast, the Gaussian prior leads to the causal SNP being declared noteworthy with very low probability.

Matched MeSH terms: Genome-Wide Association Study
Using GWAS top hits to inform priors in Bayesian fine-mapping association studies

Walters K, Cox A, Yaacob H

Genet Epidemiol, 2019 Sep;43(6):675-689.
PMID: 31286571 DOI: 10.1002/gepi.22212

The default causal single-nucleotide polymorphism (SNP) effect size prior in Bayesian fine-mapping studies is usually the Normal distribution. This choice is often based on computational convenience, rather than evidence that it is the most suitable prior distribution. The choice of prior is important because previous studies have shown considerable sensitivity of causal SNP Bayes factors to the form of the prior. In some well-studied diseases there are now considerable numbers of genome-wide association study (GWAS) top hits along with estimates of the number of yet-to-be-discovered causal SNPs. We show how the effect sizes of the top hits and estimates of the number of yet-to-be-discovered causal SNPs can be used to choose between the Laplace and Normal priors, to estimate the prior parameters and to quantify the uncertainty in this estimation. The methodology can readily be applied to other priors. We show that the top hits available from breast cancer GWAS provide overwhelming support for the Laplace over the Normal prior, which has important consequences for variant prioritisation. This work in this paper enables practitioners to derive more objective priors than are currently being used and could lead to prioritisation of different variants.

Matched MeSH terms: Genome-Wide Association Study
Fulltext Genome-Wide Novel Genic Microsatellite Marker Resource Development and Validation for Genetic Diversity and Population Structure Analysis of Banana

Biswas MK, Bagchi M, Biswas D, Harikrishna JA, Liu Y, Li C, et al.

Genes (Basel), 2020 12 09;11(12).
PMID: 33317074 DOI: 10.3390/genes11121479

Trait tagging through molecular markers is an important molecular breeding tool for crop improvement. SSR markers encoded by functionally relevant parts of a genome are well suited for this task because they may be directly related to traits. However, a limited number of these markers are known for Musa spp. Here, we report 35136 novel functionally relevant SSR markers (FRSMs). Among these, 17,561, 15,373 and 16,286 FRSMs were mapped in-silico to the genomes of Musa acuminata, M. balbisiana and M. schizocarpa, respectively. A set of 273 markers was validated using eight accessions of Musa spp., from which 259 markers (95%) produced a PCR product of the expected size and 203 (74%) were polymorphic. In-silico comparative mapping of FRSMs onto Musa and related species indicated sequence-based orthology and synteny relationships among the chromosomes of Musa and other plant species. Fifteen FRSMs were used to estimate the phylogenetic relationships among 50 banana accessions, and the results revealed that all banana accessions group into two major clusters according to their genomic background. Here, we report the first large-scale development and characterization of functionally relevant Musa SSR markers. We demonstrate their utility for germplasm characterization, genetic diversity studies, and comparative mapping in Musa spp. and other monocot species. The sequences for these novel markers are freely available via a searchable web interface called Musa Marker Database.

Matched MeSH terms: Genome-Wide Association Study/methods
Fulltext Development and Validation of an Open Access SNP Array for Nile Tilapia (Oreochromis niloticus)

Peñaloza C, Robledo D, Barría A, Trịnh TQ, Mahmuddin M, Wiener P, et al.

G3 (Bethesda), 2020 08 05;10(8):2777-2785.
PMID: 32532799 DOI: 10.1534/g3.120.401343

Tilapia are among the most important farmed fish species worldwide, and are fundamental for the food security of many developing countries. Several genetically improved Nile tilapia (Oreochromis niloticus) strains exist, such as the iconic Genetically Improved Farmed Tilapia (GIFT), and breeding programs typically follow classical pedigree-based selection. The use of genome-wide single-nucleotide polymorphism (SNP) data can enable an understanding of the genetic architecture of economically important traits and the acceleration of genetic gain via genomic selection. Due to the global importance and diversity of Nile tilapia, an open access SNP array would be beneficial for aquaculture research and production. In the current study, a ∼65K SNP array was designed based on SNPs discovered from whole-genome sequence data from a GIFT breeding nucleus population and the overlap with SNP datasets from wild fish populations and several other farmed Nile tilapia strains. The SNP array was applied to clearly distinguish between different tilapia populations across Asia and Africa, with at least ∼30,000 SNPs segregating in each of the diverse population samples tested. It is anticipated that this SNP array will be an enabling tool for population genetics and tilapia breeding research, facilitating consistency and comparison of results across studies.

Matched MeSH terms: Genome-Wide Association Study
Fulltext Genome-Wide Transcription and Functional Analyses Reveal Heterogeneous Molecular Mechanisms Driving Pyrethroids Resistance in the Major Malaria Vector Anopheles funestus Across Africa

Riveron JM, Ibrahim SS, Mulamba C, Djouaka R, Irving H, Wondji MJ, et al.

G3 (Bethesda), 2017 06 07;7(6):1819-1832.
PMID: 28428243 DOI: 10.1534/g3.117.040147

Pyrethroid resistance in malaria vector, An. funestus is increasingly reported across Africa, threatening the sustainability of pyrethroid-based control interventions, including long lasting insecticidal nets (LLINs). Managing this problem requires understanding of the molecular basis of the resistance from different regions of the continent, to establish whether it is being driven by a single or independent selective events. Here, using a genome-wide transcription profiling of pyrethroid resistant populations from southern (Malawi), East (Uganda), and West Africa (Benin), we investigated the molecular basis of resistance, revealing strong differences between the different African regions. The duplicated cytochrome P450 genes (CYP6P9a and CYP6P9b) which were highly overexpressed in southern Africa are not the most upregulated in other regions, where other genes are more overexpressed, including GSTe2 in West (Benin) and CYP9K1 in East (Uganda). The lack of directional selection on both CYP6P9a and CYP6P9b in Uganda in contrast to southern Africa further supports the limited role of these genes outside southern Africa. However, other genes such as the P450 CYP9J11 are commonly overexpressed in all countries across Africa. Here, CYP9J11 is functionally characterized and shown to confer resistance to pyrethroids and moderate cross-resistance to carbamates (bendiocarb). The consistent overexpression of GSTe2 in Benin is coupled with a role of allelic variation at this gene as GAL4-UAS transgenic expression in Drosophila flies showed that the resistant 119F allele is highly efficient in conferring both DDT and permethrin resistance than the L119. The heterogeneity in the molecular basis of resistance and cross-resistance to insecticides in An. funestus populations throughout sub-Saharan African should be taken into account in designing resistance management strategies.

Matched MeSH terms: Genome-Wide Association Study*
Fulltext Using Population and Comparative Genomics to Understand the Genetic Basis of Effector-Driven Fungal Pathogen Evolution

Plissonneau C, Benevenuto J, Mohd-Assaad N, Fouché S, Hartmann FE, Croll D

Front Plant Sci, 2017;8:119.
PMID: 28217138 DOI: 10.3389/fpls.2017.00119

Epidemics caused by fungal plant pathogens pose a major threat to agro-ecosystems and impact global food security. High-throughput sequencing enabled major advances in understanding how pathogens cause disease on crops. Hundreds of fungal genomes are now available and analyzing these genomes highlighted the key role of effector genes in disease. Effectors are small secreted proteins that enhance infection by manipulating host metabolism. Fungal genomes carry 100s of putative effector genes, but the lack of homology among effector genes, even for closely related species, challenges evolutionary and functional analyses. Furthermore, effector genes are often found in rapidly evolving chromosome compartments which are difficult to assemble. We review how population and comparative genomics toolsets can be combined to address these challenges. We highlight studies that associated genome-scale polymorphisms with pathogen lifestyles and adaptation to different environments. We show how genome-wide association studies can be used to identify effectors and other pathogenicity-related genes underlying rapid adaptation. We also discuss how the compartmentalization of fungal genomes into core and accessory regions shapes the evolution of effector genes. We argue that an understanding of genome evolution provides important insight into the trajectory of host-pathogen co-evolution.

Matched MeSH terms: Genome-Wide Association Study
Fulltext Development of High-Density SNP Markers and Their Application in Evaluating Genetic Diversity and Population Structure in Elaeis guineensis

Xia W, Luo T, Zhang W, Mason AS, Huang D, Huang X, et al.

Front Plant Sci, 2019;10:130.
PMID: 30809240 DOI: 10.3389/fpls.2019.00130

High-density single nucleotide polymorphisms (SNPs) are used as highly favored makers to analyze genetic diversity and population structure, to construct high-density genetic maps and provide genotypes for genome-wide association analysis. In order to develop genome-wide SNP markers in oil palm (Elaeis guineensis), single locus amplified fragment sequencing (SLAF-seq) technology was performed in a diversity panel of 200 oil palm individuals and 1,261,501 SNPs were identified with minor allele frequency > 0.05 and integrity > 1. Among them, only 17.81% can be mapped within the genic region and the remaining was located into the intergenic region. A positive correlation was detected between the distribution of SNP markers and retrotransposons [transposable elements (TEs)]. Population structure analysis showed that the 200 individuals of oil palm can be divided into five subgroups based on cross-validation errors. However, the subpopulations divided for the 200 oil palm individuals based on the SNP markers were not accurately related to their geographical origins and 80 oil palm individuals from Malaysia showed highest genetic diversity. In addition, the physical distance of linkage disequilibrium (LD) decay in the analyzed oil palm population was 14.516 kb when r2 = 0.1. The LD decay distances for different chromosomes varied from 3.324 (chromosome 15) to 19.983 kb (chromosome 7). Our research provides genome-wide SNPs for future targeted breeding in palm oil.

Matched MeSH terms: Genome-Wide Association Study
Identification of Copy Number Variation Among Nonsyndromic Cleft Lip and or Without Cleft Palate With Hypodontia: A Genome-Wide Association Study

Ghazali N, Abd Rahman N, Ahmad A, Sulong S, Kannan TP

Front Physiol, 2021;12:637306.
PMID: 33732167 DOI: 10.3389/fphys.2021.637306

Nonsyndromic cleft lip and or without cleft palate (NSCL/P) with the hypodontia is a common developmental abnormality in humans and animals. This study identified the genetic aberration involved in both NSCL/P and hypodontia pathogenesis. A cross-sectional study using genome-wide study copy number variation-targeted CytoScan 750K array carried out on salivary samples from 61 NSCL/P and 20 noncleft with and without hypodontia Malay subjects aged 7-13 years old. Copy number variations (CNVs) of SKI and fragile histidine triad (FHIT) were identified in NSCL/P and noncleft children using quantitative polymerase chain reaction (qPCR) as a validation analysis. Copy number calculated (CNC) for each gene determined with Applied Biosystems CopyCaller Software v2.0. The six significant CNVs included gains (12q14.3, 15q26.3, 1p36.32, and 1p36.33) and losses (3p14.2 and 4q13.2) in NSCL/P with hypodontia patients compared with the NSCL/P only. The genes located in these regions encoded LEMD3, IGF1R, TP73, SKI, FHIT, and UGT2β15. There were a significant gain and loss of both SKI and FHIT copy number in NSCL/P with hypodontia compared with the noncleft group (p < 0.05). The results supported that CNVs significantly furnish to the development of NSCL/P with hypodontia.

Matched MeSH terms: Genome-Wide Association Study
Combining Understanding of Immunological Mechanisms and Genetic Variants Toward Development of Personalized Medicine for Psoriasis Patients

Gunter NV, Yap BJM, Chua CLL, Yap WH

Front Genet, 2019;10:395.
PMID: 31130981 DOI: 10.3389/fgene.2019.00395

Psoriasis is multifactorial disease with complex genetic predisposition. Recent advances in genetics and genomics analyses have provided many insights into the relationship between specific genetic predisposition and the immunopathological mechanisms driving psoriasis manifestation. Novel approaches which utilize array-based genotyping technologies such as genome-wide association studies and bioinformatics tools for transcriptomics analysis have identified single nucleotide polymorphisms, genes and pathways that are associated with psoriasis. The discovery of these psoriasis-associated susceptibility loci, autoimmune targets and altered signaling pathways have provided opportunities to bridge the gap of knowledge from sequence to consequence, allowing new therapeutic strategies for the treatment of psoriasis to be developed. Here, we discuss recent advances in the field by highlighting how immune functions associated with psoriasis susceptibility loci may contribute to disease pathogenesis in different populations. Understanding the genetic variations in psoriasis and how these may influence the immunological pathways to cause disease will contribute to the efforts in developing novel and targeted personalized therapies for psoriasis patients.

Matched MeSH terms: Genome-Wide Association Study
Fulltext A genome-wide pleiotropy scan for prostate cancer risk

Panagiotou OA, Travis RC, Campa D, Berndt SI, Lindstrom S, Kraft P, et al.

Eur Urol, 2015 Apr;67(4):649-57.
PMID: 25277271 DOI: 10.1016/j.eururo.2014.09.020

BACKGROUND: No single-nucleotide polymorphisms (SNPs) specific for aggressive prostate cancer have been identified in genome-wide association studies (GWAS).
OBJECTIVE: To test if SNPs associated with other traits may also affect the risk of aggressive prostate cancer.
DESIGN, SETTING, AND PARTICIPANTS: SNPs implicated in any phenotype other than prostate cancer (p≤10(-7)) were identified through the catalog of published GWAS and tested in 2891 aggressive prostate cancer cases and 4592 controls from the Breast and Prostate Cancer Cohort Consortium (BPC3). The 40 most significant SNPs were followed up in 4872 aggressive prostate cancer cases and 24,534 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) and 95% confidence intervals (CIs) for aggressive prostate cancer were estimated.
RESULTS AND LIMITATIONS: A total of 4666 SNPs were evaluated by the BPC3. Two signals were seen in regions already reported for prostate cancer risk. rs7014346 at 8q24.21 was marginally associated with aggressive prostate cancer in the BPC3 trial (p=1.6×10(-6)), whereas after meta-analysis by PRACTICAL the summary OR was 1.21 (95% CI 1.16-1.27; p=3.22×10(-18)). rs9900242 at 17q24.3 was also marginally associated with aggressive disease in the meta-analysis (OR 0.90, 95% CI 0.86-0.94; p=2.5×10(-6)). Neither of these SNPs remained statistically significant when conditioning on correlated known prostate cancer SNPs. The meta-analysis by BPC3 and PRACTICAL identified a third promising signal, marked by rs16844874 at 2q34, independent of known prostate cancer loci (OR 1.12, 95% CI 1.06-1.19; p=4.67×10(-5)); it has been shown that SNPs correlated with this signal affect glycine concentrations. The main limitation is the heterogeneity in the definition of aggressive prostate cancer between BPC3 and PRACTICAL.
CONCLUSIONS: We did not identify new SNPs for aggressive prostate cancer. However, rs16844874 may provide preliminary genetic evidence on the role of the glycine pathway in prostate cancer etiology.
PATIENT SUMMARY: We evaluated whether genetic variants associated with several traits are linked to the risk of aggressive prostate cancer. No new such variants were identified.

Matched MeSH terms: Genome-Wide Association Study/methods*
Fulltext Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma

Machiela MJ, Hofmann JN, Carreras-Torres R, Brown KM, Johansson M, Wang Z, et al.

Eur Urol, 2017 Nov;72(5):747-754.
PMID: 28797570 DOI: 10.1016/j.eururo.2017.07.015

BACKGROUND: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings.
OBJECTIVE: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.
DESIGN, SETTING, AND PARTICIPANTS: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis.
RESULTS AND LIMITATIONS: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13).
CONCLUSIONS: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk.
PATIENT SUMMARY: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.

Matched MeSH terms: Genome-Wide Association Study

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