scholarly journals Genome-wide association studies for methane emission and ruminal volatile fatty acids using Holstein cattle sequence data

2020 ◽  
Author(s):  
Ali Jalil Sarghale ◽  
Mohammad Moradi Shahrebabak ◽  
Hossein Moradi Shahrebabak ◽  
Ardeshir Nejati Javaremi ◽  
Mahdi Saatchi ◽  
...  
Keyword(s):  
Methane Emission ◽  
Feed Intake ◽  
Volatile Fatty Acids ◽  
Sequence Data ◽  
Association Studies ◽  
Olfactory Receptors ◽  
Significant Snps ◽  
Valeric Acid ◽  
Genome Wide Association Studies ◽  
Genome Wide

Abstract Background: Methane emission by ruminants has contributed considerably to the global warming and understanding the genomic architecture of methane production may help the livestock producers to reduce the methane emission from the livestock production system. The goal of our study was to identify genomic regions affecting the predicted methane emission (PME) from volatile fatty acids (VFAs) indicators and VFA traits using imputed whole-genome sequence data in Iranian Holstein cattle. Results: Based on the significant-association threshold (p < 5 × 10−8), 33 single nucleotide polymorphisms (SNPs) were detected for PME per kg milk (n=2), PME per kg fat (n=14), and valeric acid (n=17). Besides, 69 genes were identified for valeric acid (n=18), PME per kg milk (n=4) and PME per kg fat (n=47) that were located within 1 Mb of significant SNPs. Based on the gene ontology (GO) term analysis, six promising candidate genes were significantly clustered in organelle organization (GO:0004984, p = 3.9 × 10-2) for valeric acid, and 17 candidate genes significantly clustered in olfactory receptors activity (GO:0004984, p = 4 × 10-10) for PME traits. Annotation results revealed 31 quantitative trait loci (QTLs) for milk yield and its components, body weight, and residual feed intake within 1 Mb of significant SNPs. Conclusions: Our results identified 33 SNPs associated with PME and valeric acid traits, as well as 17 olfactory receptors activity genes for PME traits related to food preference and feed intake. Identified SNPs in this study were close to 31 QTLs for milk yield and its components, body weight, and residual feed intake traits. In addition, these traits had high correlations with PME trait. Overall, our findings suggest that marker-assisted and genomic selection could be used to improve the difficult and expensive-to-measure phenotypes such as PME. Moreover, prediction of methane emission by VFA indicators could be useful for increasing the size of the reference population required in genome-wide association studies and genomic selection.

scholarly journals Genome-wide association studies for methane emission and ruminal volatile fatty acids using Holstein cattle sequence data

BMC Genetics ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Ali Jalil Sarghale ◽  
Mohammad Moradi Shahrebabak ◽  
Hossein Moradi Shahrebabak ◽  
Ardeshir Nejati Javaremi ◽  
Mahdi Saatchi ◽  
...  
Keyword(s):  
Methane Emission ◽  
Feed Intake ◽  
Volatile Fatty Acids ◽  
Sequence Data ◽  
Association Studies ◽  
Olfactory Receptors ◽  
Significant Snps ◽  
Valeric Acid ◽  
Genome Wide Association Studies ◽  
Genome Wide

Abstract Background Methane emission by ruminants has contributed considerably to the global warming and understanding the genomic architecture of methane production may help livestock producers to reduce the methane emission from the livestock production system. The goal of our study was to identify genomic regions affecting the predicted methane emission (PME) from volatile fatty acids (VFAs) indicators and VFA traits using imputed whole-genome sequence data in Iranian Holstein cattle. Results Based on the significant-association threshold (p < 5 × 10− 8), 33 single nucleotide polymorphisms (SNPs) were detected for PME per kg milk (n = 2), PME per kg fat (n = 14), and valeric acid (n = 17). Besides, 69 genes were identified for valeric acid (n = 18), PME per kg milk (n = 4) and PME per kg fat (n = 47) that were located within 1 Mb of significant SNPs. Based on the gene ontology (GO) term analysis, six promising candidate genes were significantly clustered in organelle organization (GO:0004984, p = 3.9 × 10− 2) for valeric acid, and 17 candidate genes significantly clustered in olfactory receptors activity (GO:0004984, p = 4 × 10− 10) for PME traits. Annotation results revealed 31 quantitative trait loci (QTLs) for milk yield and its components, body weight, and residual feed intake within 1 Mb of significant SNPs. Conclusions Our results identified 33 SNPs associated with PME and valeric acid traits, as well as 17 olfactory receptors activity genes for PME traits related to feed intake and preference. Identified SNPs were close to 31 QTLs for milk yield and its components, body weight, and residual feed intake traits. In addition, these traits had high correlations with PME trait. Overall, our findings suggest that marker-assisted and genomic selection could be used to improve the difficult and expensive-to-measure phenotypes such as PME. Moreover, prediction of methane emission by VFA indicators could be useful for increasing the size of reference population required in genome-wide association studies and genomic selection.

scholarly journals Genome-wide association studies for methane emission and ruminal volatile fatty acids using Holstein cattle sequence data

2020 ◽  
Author(s):  
Ali Jalil Sarghale ◽  
Mohammad Moradi Shahrebabak ◽  
Hossein Moradi Shahrebabak ◽  
Ardeshir Nejati Javaremi ◽  
Mahdi Saatchi ◽  
...  
Keyword(s):  
Methane Emission ◽  
Feed Intake ◽  
Volatile Fatty Acids ◽  
Sequence Data ◽  
Association Studies ◽  
Olfactory Receptors ◽  
Significant Snps ◽  
Valeric Acid ◽  
Genome Wide Association Studies ◽  
Genome Wide

Abstract Background: Methane emission by ruminants has contributed considerably to the global warming and understanding the genomic architecture of methane production may help the livestock producers to reduce the methane emission from the livestock production system. The goal of our study was to identify genomic regions affecting the predicted methane emission (PME) from volatile fatty acids (VFAs) indicators and VFA traits using imputed whole-genome sequence data in Iranian Holstein cattle.Results: Based on the significant-association threshold (p < 5 × 10−8), 33 single nucleotide polymorphisms (SNPs) were detected for PME per kg milk (n=2), PME per kg fat (n=14), and valeric acid (n=17). Besides, 69 genes were identified for valeric acid (n=18), PME per kg milk (n=4) and PME per kg fat (n=47) that were located within 1 Mb of significant SNPs. Based on the gene ontology (GO) term analysis, six promising candidate genes were significantly clustered in organelle organization (GO:0004984, p = 3.9 × 10-2) for valeric acid, and 17 candidate genes significantly clustered in olfactory receptors activity (GO:0004984, p = 4 × 10-10) for PME traits. Annotation results revealed 31 quantitative trait loci (QTLs) for milk yield and its components, body weight, and residual feed intake within 1 Mb of significant SNPs.Conclusions:Our results identified 33 SNPs associated with PME and valeric acid traits, as well as 17 olfactory receptors activity genes for PME traits related to food preference and feed intake. Identified SNPs in this study were close to 31 QTLs for milk yield and its components, body weight, and residual feed intake traits. In addition, these traits had high correlations with PME trait. Overall, our findings suggest that marker-assisted and genomic selection could be used to improve the difficult and expensive-to-measure phenotypes such as PME. Moreover, prediction of methane emission by VFA indicators could be useful for increasing the size of the reference population required in genome-wide association studies and genomic selection.

scholarly journals Genome-wide association studies for methane emission and ruminal volatile fatty acids using Holstein cattle sequence data

2020 ◽  
Author(s):  
Ali Jalil Sarghale ◽  
Mohammad Moradi Shahrebabak ◽  
Hossein Moradi Shahrebabak ◽  
Ardeshir Nejati Javaremi ◽  
Mahdi Saatchi ◽  
...  
Keyword(s):  
Methane Emission ◽  
Feed Intake ◽  
Volatile Fatty Acids ◽  
Sequence Data ◽  
Association Studies ◽  
Olfactory Receptors ◽  
Significant Snps ◽  
Valeric Acid ◽  
Genome Wide Association Studies ◽  
Genome Wide

Abstract Background: Methane emission by ruminants has contributed considerably to the global warming and understanding the genomic architecture of methane production may help the livestock producers to reduce the methane emission from the livestock production system. The goal of our study was to identify genomic regions affecting the predicted methane emission (PME) from volatile fatty acids (VFAs) indicators and VFA traits using imputed whole-genome sequence data in Iranian Holstein cattle. Results: Based on the significant-association threshold ( p < 5 × 10 −8 ), 33 single nucleotide polymorphisms (SNPs) were detected for PME per kg milk (n=2), PME per kg fat (n=14), and valeric acid (n=17). Besides, 69 genes were identified for valeric acid (n=18), PME per kg milk (n=4) and PME per kg fat (n=47) that were located within 1 Mb of significant SNPs. Based on the gene ontology (GO) term analysis, six promising candidate genes were significantly clustered in organelle organization (GO:0004984, p = 3.9 × 10 -2 ) for valeric acid, and 17 candidate genes significantly clustered in olfactory receptors activity (GO:0004984, p = 4 × 10 -10 ) for PME traits. Annotation results revealed 31 quantitative trait loci (QTLs) for milk yield and its components, body weight, and residual feed intake within 1 Mb of significant SNPs. Conclusions: Our results identified 33 SNPs associated with PME and valeric acid traits, as well as 17 olfactory receptors activity genes for PME traits related to food preference and feed intake. Identified SNPs in this study were close to 31 QTLs for milk yield and its components, body weight, and residual feed intake traits. In addition, these traits had high correlations with PME trait. Overall, our findings suggest that marker-assisted and genomic selection could be used to improve the difficult and expensive-to-measure phenotypes such as PME. Moreover, prediction of methane emission by VFA indicators could be useful for increasing the size of the reference population required in genome-wide association studies and genomic selection.

scholarly journals Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

Nature ◽  
2021 ◽  
Vol 590 (7845) ◽  
pp. 290-299 ◽  
Author(s):  
Daniel Taliun ◽  
◽  
Daniel N. Harris ◽  
Michael D. Kessler ◽  
Jedidiah Carlson ◽  
...  
Keyword(s):  
Rare Variants ◽  
Sequence Data ◽  
Association Studies ◽  
Genotype Imputation ◽  
Genome Wide Association Studies ◽  
Phenotypic Data ◽  
Treatment And Prevention ◽  
Genome Wide ◽  
Diverse Backgrounds ◽  
Unmapped Reads

AbstractThe Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

scholarly journals Estimating Effect Sizes and Expected Replication Probabilities from GWAS Summary Statistics

2015 ◽  
Author(s):  
Dominic Holland ◽  
Yunpeng Wang ◽  
Wesley K Thompson ◽  
Andrew Schork ◽  
Chi-Hua Chen ◽  
...  
Keyword(s):  
Association Studies ◽  
Significant Snps ◽  
Effect Sizes ◽  
Genome Wide Association Studies ◽  
Summary Statistics ◽  
Sample Sizes ◽  
Genetic Components ◽  
Complex Phenotypes ◽  
Genome Wide ◽  
Z Scores

Genome-wide Association Studies (GWAS) result in millions of summary statistics (``z-scores'') for single nucleotide polymorphism (SNP) associations with phenotypes. These rich datasets afford deep insights into the nature and extent of genetic contributions to complex phenotypes such as psychiatric disorders, which are understood to have substantial genetic components that arise from very large numbers of SNPs. The complexity of the datasets, however, poses a significant challenge to maximizing their utility. This is reflected in a need for better understanding the landscape of z-scores, as such knowledge would enhance causal SNP and gene discovery, help elucidate mechanistic pathways, and inform future study design. Here we present a parsimonious methodology for modeling effect sizes and replication probabilities that does not require raw genotype data, relying only on summary statistics from GWAS substudies, and a scheme allowing for direct empirical validation. We show that modeling z-scores as a mixture of Gaussians is conceptually appropriate, in particular taking into account ubiquitous non-null effects that are likely in the datasets due to weak linkage disequilibrium with causal SNPs. The four-parameter model allows for estimating the degree of polygenicity of the phenotype -- the proportion of SNPs (after uniform pruning, so that large LD blocks are not over-represented) likely to be in strong LD with causal/mechanistically associated SNPs -- and predicting the proportion of chip heritability explainable by genome wide significant SNPs in future studies with larger sample sizes. We apply the model to recent GWAS of schizophrenia (N=82,315) and additionally, for purposes of illustration, putamen volume (N=12,596), with approximately 9.3 million SNP z-scores in both cases. We show that, over a broad range of z-scores and sample sizes, the model accurately predicts expectation estimates of true effect sizes and replication probabilities in multistage GWAS designs. We estimate the degree to which effect sizes are over-estimated when based on linear regression association coefficients. We estimate the polygenicity of schizophrenia to be 0.037 and the putamen to be 0.001, while the respective sample sizes required to approach fully explaining the chip heritability are 106and 105. The model can be extended to incorporate prior knowledge such as pleiotropy and SNP annotation. The current findings suggest that the model is applicable to a broad array of complex phenotypes and will enhance understanding of their genetic architectures.

scholarly journals Genome-Wide Association Studies for the Concentration of Albumin in Colostrum and Serum in Chinese Holstein

Animals ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 2211
Author(s):  
Shan Lin ◽  
Zihui Wan ◽  
Junnan Zhang ◽  
Lingna Xu ◽  
Bo Han ◽  
...  
Keyword(s):  
Association Studies ◽  
Significant Snps ◽  
Albumin Concentration ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Chinese Holstein ◽  
Genome Wide ◽  
Chinese Holstein Cows ◽  
Newborn Calves

Albumin can be of particular benefit in fighting infections for newborn calves due to its anti-inflammatory and anti-oxidative stress properties. To identify the candidate genes related to the concentration of albumin in colostrum and serum, we collected the colostrum and blood samples from 572 Chinese Holstein cows within 24 h after calving and measured the concentration of albumin in the colostrum and serum using the ELISA methods. The cows were genotyped with GeneSeek 150 K chips (containing 140,668 single nucleotide polymorphisms; SNPs). After quality control, we performed GWASs via GCTA software with 91,620 SNPs and 563 cows. Consequently, 9 and 7 genome-wide significant SNPs (false discovery rate (FDR) at 1%) were identified. Correspondingly, 42 and 206 functional genes that contained or were approximate to (±1 Mbp) the significant SNPs were acquired. Integrating the biological process of these genes and the reported QTLs for immune and inflammation traits in cattle, 3 and 12 genes were identified as candidates for the concentration of colostrum and serum albumin, respectively; these are RUNX1, CBR1, OTULIN,CDK6, SHARPIN, CYC1, EXOSC4, PARP10, NRBP2, GFUS, PYCR3, EEF1D, GSDMD, PYCR2 and CXCL12. Our findings provide important information for revealing the genetic mechanism behind albumin concentration and for molecular breeding of disease-resistance traits in dairy cattle.

scholarly journals Educational attainment impacts drinking behaviors and risk for alcohol dependence: results from a two-sample Mendelian randomization study with ~780,000 participants

2019 ◽  
Author(s):  
Daniel B. Rosoff ◽  
Toni-Kim Clarke ◽  
Mark J. Adams ◽  
Andrew M. McIntosh ◽  
George Davey Smith ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Educational Attainment ◽  
Alcohol Dependence ◽  
Mendelian Randomization ◽  
Association Studies ◽  
Significant Snps ◽  
Genome Wide Association Studies ◽  
Reverse Causality ◽  
Genome Wide ◽  
Genetic Instruments

Abstract Observational studies suggest that lower educational attainment (EA) may be associated with risky alcohol use behaviors; however, these findings may be biased by confounding and reverse causality. We performed two-sample Mendelian randomization (MR) using summary statistics from recent genome-wide association studies (GWAS) with >780,000 participants to assess the causal effects of EA on alcohol use behaviors and alcohol dependence (AD). Fifty-three independent genome-wide significant SNPs previously associated with EA were tested for association with alcohol use behaviors. We show that while genetic instruments associated with increased EA are not associated with total amount of weekly drinks, they are associated with reduced frequency of binge drinking ≥6 drinks (ßIVW = −0.198, 95% CI, −0.297 to –0.099, PIVW = 9.14 × 10−5), reduced total drinks consumed per drinking day (ßIVW = −0.207, 95% CI, −0.293 to –0.120, PIVW = 2.87 × 10−6), as well as lower weekly distilled spirits intake (ßIVW = −0.148, 95% CI, −0.188 to –0.107, PIVW = 6.24 × 10−13). Conversely, genetic instruments for increased EA were associated with increased alcohol intake frequency (ßIVW = 0.331, 95% CI, 0.267–0.396, PIVW = 4.62 × 10−24), and increased weekly white wine (ßIVW = 0.199, 95% CI, 0.159–0.238, PIVW = 7.96 × 10−23) and red wine intake (ßIVW = 0.204, 95% CI, 0.161–0.248, PIVW = 6.67 × 10−20). Genetic instruments associated with increased EA reduced AD risk: an additional 3.61 years schooling reduced the risk by ~50% (ORIVW = 0.508, 95% CI, 0.315–0.819, PIVW = 5.52 × 10−3). Consistency of results across complementary MR methods accommodating different assumptions about genetic pleiotropy strengthened causal inference. Our findings suggest EA may have important effects on alcohol consumption patterns and may provide potential mechanisms explaining reported associations between EA and adverse health outcomes.

scholarly journals Genome-Wide Meta-Analysis of Late-Onset Alzheimer's Disease Using Rare Variant Imputation in 324,809 Subjects Identifies Novel Rare Variant Locus NCK2: The International Genomics of Alzheimer's Project (IGAP)

2021 ◽  
Author(s):  
Adam C. Naj ◽  
Ganna Leonenko ◽  
Xueqiu Jian ◽  
Benjamin Grenier-Boley ◽  
Maria Carolina Dalmasso ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rare Variant ◽  
Late Onset ◽  
Sequence Data ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
The Uk

Risk for late-onset Alzheimer's disease (LOAD) is driven by multiple loci primarily identified by genome-wide association studies, many of which are common variants with minor allele frequencies (MAF)>0.01. To identify additional common and rare LOAD risk variants, we performed a GWAS on 25,170 LOAD subjects and 41,052 cognitively normal controls in 44 datasets from the International Genomics of Alzheimer's Project (IGAP). Existing genotype data were imputed using the dense, high-resolution Haplotype Reference Consortium (HRC) r1.1 reference panel. Stage 1 associations of P<10-5 were meta-analyzed with the European Alzheimer's Disease Biobank (EADB) (n=20,301 cases; 21,839 controls) (stage 2 combined IGAP and EADB). An expanded meta-analysis was performed using a GWAS of parental AD/dementia history in the UK Biobank (UKBB) (n=35,214 cases; 180,791 controls) (stage 3 combined IGAP, EADB, and UKBB). Common variant (MAF≥0.01) associations were identified for 29 loci in stage 2, including novel genome-wide significant associations at TSPAN14 (P=2.33×10-12), SHARPIN (P=1.56×10-9), and ATF5/SIGLEC11 (P=1.03[mult]10-8), and newly significant associations without using AD proxy cases in MTSS1L/IL34 (P=1.80×10-8), APH1B (P=2.10×10-13), and CLNK (P=2.24×10-10). Rare variant (MAF<0.01) associations with genome-wide significance in stage 2 included multiple variants in APOE and TREM2, and a novel association of a rare variant (rs143080277; MAF=0.0054; P=2.69×10-9) in NCK2, further strengthened with the inclusion of UKBB data in stage 3 (P=7.17×10-13). Single-nucleus sequence data shows that NCK2 is highly expressed in amyloid-responsive microglial cells, suggesting a role in LOAD pathology.

scholarly journals Sequencing of over 100,000 individuals identifies multiple genes and rare variants associated with Crohns disease susceptibility

2021 ◽  
Author(s):  
Aleksejs Sazonovs ◽  
Christine R Stevens ◽  
Guhan R Venkataraman ◽  
Kai Yuan ◽  
Brandon Avila ◽  
...  
Keyword(s):  
Rare Variants ◽  
Disease Risk ◽  
Sequence Data ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Crohns Disease ◽  
Biological Targets ◽  
Genome Wide ◽  
Coding Variants ◽  
First Time

Genome-wide association studies (GWAS) have identified hundreds of loci associated with Crohns disease (CD); however, as with all complex diseases, deriving pathogenic mechanisms from these non-coding GWAS discoveries has been challenging. To complement GWAS and better define actionable biological targets, we analysed sequence data from more than 30,000 CD cases and 80,000 population controls. We observe rare coding variants in established CD susceptibility genes as well as ten genes where coding variation directly implicates the gene in disease risk for the first time.

scholarly journals Genome-wide Identification of Powdery Mildew Resistance in Common Bean

2020 ◽  
Author(s):  
Papias Hongera Binagwa ◽  
Sy M. Traore ◽  
Marceline Egnin ◽  
Gregory C. Bernard ◽  
Inocent Ritte ◽  
...  
Keyword(s):  
Disease Resistance ◽  
Common Bean ◽  
Resistance Genes ◽  
Agronomic Traits ◽  
Association Studies ◽  
Significant Snps ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Disease Resistance Protein ◽  
Resistance Protein

Abstract Background: Genome-wide association studies (GWAS) was utilized to detect genetic variations related to the powdery mildew (PM) resistance and several agronomic traits in common bean. However, its application in common bean and the PM interactions to identify genes and their location in the common bean genome has not been fully addressed. Results: Genome-wide association studies (GWAS) through marker-trait association are useful molecular tools for the identification of disease resistance and other agronomic traits. SNP genotyping with a BeadChip containing 5398 SNPs was used to detect genetic variations related to resistance to PM disease in a panel of 206 genotypes grown under field conditions for two consecutive years. Significant SNPs identified on chromosomes 4 and 10 (Pv04 and Pv10) were repeatable, confirming the reliability of the phenotypic data scored from the genotypes grown in two locations within two years. A cluster of resistance genes was revealed on the chromosome 4 of common bean genome among which CNL and TNL like resistance genes were identified. Furthermore, two resistance genes Phavu_010G1320001g and Phavu_010G136800g were also identified on Pv10; further sequence analysis showed that these genes were homologs to the Arabidopsis disease resistance protein (RLM1A-like) and the putative disease resistance protein (At4g11170.1), respectively. Two LRR receptor-like kinases (RLK) were also identified on Pv11 in samples collected in 2018 only. Many genes encoding auxin-responsive protein, TIFY10A protein, growth-regulating factor 5-like, ubiquitin-like protein, cell wall protein RBR3-like protein related to PM resistance were identified nearby significant SNPs. These results suggested that the resistance to PM pathogen involves a network of many genes constitutively co-expressed and may generate several layers of defense barriers or inducible reactions.Conclusion: Our results provide new insights into common bean and PM interactions, and revealed putative resistance genes as well as their location on common bean genome that could be used for marker-assisted selection, functional genomic study approaches to confirm the role of these putative genes; hence, developing common bean resistance lines to the PM disease.

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