Browsing by Subject "RARE"

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  • Kun-Rodrigues, Celia; Orme, Tatiana; Carmona, Susana; Hernandez, Dena G.; Ross, Owen A.; Eicher, John D.; Shepherd, Claire; Parkkinen, Laura; Darwent, Lee; Heckman, Michael G.; Scholz, Sonja W.; Troncoso, Juan C.; Pletnikova, Olga; Dawson, Ted; Rosenthal, Liana; Ansorge, Olaf; Clarimonm, Jordi; Lleo, Alberto; Morenas-Rodriguez, Estrella; Clark, Lorraine; Honig, Lawrence S.; Marder, Karen; Lemstra, Afina; Rogaeva, Ekaterina; St George-Hyslop, Peter; Londos, Elisabet; Zetterberg, Henrik; Barber, Imelda; Braae, Anne; Brown, Kristelle; Morgan, Kevin; Troakes, Claire; Al-Sarraj, Safa; Lashley, Tammaryn; Holton, Janice; Compta, Yaroslau; Van Deerlin, Vivianna; Serrano, Geidy E.; Beach, Thomas G.; Lesage, Suzanne; Galasko, Douglas; Masliah, Eliezer; Santana, Isabel; Pastor, Pau; Diez-Fairen, Monica; Aguilar, Miquel; Tienari, Pentti J.; Myllykangas, Liisa; Oinas, Minna; Revesz, Tamas; Lees, Andrew; Boeve, Brad F.; Petersen, Ronald C.; Ferman, Tanis J.; Escott-Price, Valentina; Graff-Radford, Neill; Cairns, Nigel J.; Morris, John C.; Pickering-Brown, Stuart; Mann, David; Halliday, Glenda M.; Hardy, John; Trojanowski, John Q.; Dickson, Dennis W.; Singleton, Andrew; Stone, David J.; Guerreiro, Rita; Bras, Jose (2019)
    The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk. (C) 2019 Elsevier Inc. All rights reserved.
  • Smaragdov, M. G.; Kudinov, A. A. (2020)
    Background Due to the advent of SNP array technology, a genome-wide analysis of genetic differences between populations and breeds has become possible at a previously unattainable level. The Wright's fixation index (F-st) and the principal component analysis (PCA) are widely used methods in animal genetics studies. In paper we compared the power of these methods, their complementing each other and which of them is the most powerful. Results Comparative analysis of the power Principal Components Analysis (PCA) and F-st were carried out to reveal genetic differences between herds of Holsteinized cows. Totally, 803 BovineSNP50 genotypes of cows from 13 herds were used in current study. Obtained F-st values were in the range of 0.002-0.012 (mean 0.0049) while for rare SNPs with MAF 0.0001-0.005 they were even smaller in the range of 0.001-0.01 (mean 0.0027). Genetic relatedness of the cows in the herds was the cause of such small F-st values. The contribution of rare alleles with MAF 0.0001-0.01 to the F-st values was much less than common alleles and this effect depends on linkage disequilibrium (LD). Despite of substantial change in the MAF spectrum and the number of SNPs we observed small effect size of LD - based pruning on F-st data. PCA analysis confirmed the mutual admixture and small genetic difference between herds. Moreover, PCA analysis of the herds based on the visualization the results of a single eigenvector cannot be used to significantly differentiate herds. Only summed eigenvectors should be used to realize full power of PCA to differentiate small between herds genetic difference. Finally, we presented evidences that the significance of F-st data far exceeds the significance of PCA data when these methods are used to reveal genetic differences between herds. Conclusions LD - based pruning had a small effect on findings of F-st and PCA analyzes. Therefore, for weakly structured populations the LD - based pruning is not effective. In addition, our results show that the significance of genetic differences between herds obtained by F-st analysis exceeds the values of PCA. Proposed, to differentiate herds or low structured populations we recommend primarily using the F-st approach and only then PCA.
  • Spracklen, Cassandra N.; Karaderi, Tugce; Yaghootkar, Hanieh; Schurmann, Claudia; Fine, Rebecca S.; Kutalik, Zoltan; Preuss, Michael H.; Lu, Yingchang; Wittemans, Laura B. L.; Adair, Linda S.; Allison, Matthew; Amin, Najaf; Auer, Paul L.; Bartz, Traci M.; Blueher, Matthias; Boehnke, Michael; Borja, Judith B.; Bork-Jensen, Jette; Broer, Linda; Chasman, Daniel I.; Chen, Yii-Der Ida; Chirstofidou, Paraskevi; Demirkan, Ayse; van Duijn, Cornelia M.; Feitosa, Mary F.; Garcia, Melissa E.; Graff, Mariaelisa; Grallert, Harald; Grarup, Niels; Guo, Xiuqing; Haesser, Jeffrey; Hansen, Torben; Harris, Tamara B.; Highland, Heather M.; Hong, Jaeyoung; Ikram, M. Arfan; Ingelsson, Erik; Jackson, Rebecca; Jousilahti, Pekka; Kahonen, Mika; Kizer, Jorge R.; Kovacs, Peter; Kriebel, Jennifer; Laakso, Markku; Lange, Leslie A.; Lehtimaki, Terho; Li, Jin; Ruifang Li-Gao; Lind, Lars; Luan, Jian'an; Lyytikainen, Leo-Pekka; MacGregor, Stuart; Mackey, David A.; Mahajan, Anubha; Mangino, Massimo; Männistö, Satu; McCarthy, Mark I.; McKnight, Barbara; Medina-Gomez, Carolina; Meigs, James B.; Molnos, Sophie; Mook-Kanamori, Dennis; Morris, Andrew P.; de Mutsert, Renee; Nalls, Mike A.; Nedeljkovic, Ivana; North, Kari E.; Pennell, Craig E.; Pradhan, Aruna D.; Province, Michael A.; Raitakari, Olli T.; Raulerson, Chelsea K.; Reiner, Alex P.; Ridker, Paul M.; Ripatti, Samuli; Roberston, Neil; Rotter, Jerome I.; Salomaa, Veikko; Sandoval-Zarate, America A.; Sitlani, Colleen M.; Spector, Tim D.; Strauch, Konstantin; Stumvoll, Michael; Taylor, Kent D.; Thuesen, Betina; Toenjes, Anke; Uitterlinden, Andre G.; Venturini, Cristina; Walker, Mark; Wang, Carol A.; Wang, Shuai; Wareham, Nicholas J.; Willems, Sara M.; van Dijk, Ko Willems; Wilson, James G.; Wu, Ying; Yao, Jie; Young, Kristin L.; Langenberg, Claudia; Frayling, Timothy M.; Kilpelainen, Tuomas O.; Lindgren, Cecilia M.; Loos, Ruth J. F.; Mohlke, Karen L. (2019)
    Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p <2 x 10(-7)). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r(2) > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p <1 x 10(-4)) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.
  • Kerminen, Sini; Havulinna, Aki S.; Hellenthal, Garrett; Martin, Alicia R.; Sarin, Antti-Pekka; Perola, Markus; Palotie, Aarno; Salomaa, Veikko; Daly, Mark J.; Ripatti, Samuli; Pirinen, Matti (2017)
    Coupling dense genotype data with new computational methods offers unprecedented opportunities for individual-level ancestry estimation once geographically precisely defined reference data sets become available. We study such a reference data set for Finland containing 2376 such individuals from the FINRISK Study survey of 1997 both of whose parents were born close to each other. This sampling strategy focuses on the population structure present in Finland before the 1950s. By using the recent haplotype-based methods ChromoPainter (CP) and FineSTRUCTURE (FS) we reveal a highly geographically clustered genetic structure in Finland and report its connections to the settlement history as well as to the current dialectal regions of the Finnish language. The main genetic division within Finland shows striking concordance with the 1323 borderline of the treaty of Noteborg. In general, we detect genetic substructure throughout the country, which reflects stronger regional genetic differences in Finland compared to, for example, the UK, which in a similar analysis was dominated by a single unstructured population. We expect that similar population genetic reference data sets will become available for many more populations in the near future with important applications, for example, in forensic genetics and in genetic association studies. With this in mind, we report those extensions of the CP + FS approach that we found most useful in our analyses of the Finnish data.
  • UWCMG (2018)
    Non-secretor status due tohomozygosity for the commonFUT2 variant c. 461G> A(p. Trp154*) is associated witheither risk for autoimmune diseases or protection against viral diarrhea and HIV. We determined the role of FUT2 in otitis media susceptibility by obtaining DNA samples from 609 multi-ethnic families and simplex case subjectswith otitis media. Exome and Sanger sequencing, linkage analysis, and Fisher exact and transmission disequilibrium tests (TDT) were performed. The common FUT2 c. 604C> T (p. Arg202*) variant co-segregates with otitismedia in a Filipino pedigree (LOD = 4.0). Additionally, a rare variant, c. 412C> T (p. Arg138Cys), is associated with recurrent/ chronic otitismedia in European-American children (p = 1.2310(-5)) and US trios (TDT p = 0.01). The c. 461G> A (p. Trp154*) variant was also overtransmitted in US trios (TDT p = 0.01) and was associated with shifts inmiddle ear microbiota composition (PERMANOVA p <10(-7)) and increased biodiversity. When all missense and nonsense variants identified in multi-ethnic US trios withCADD> 20 were combined, FUT2 variantswere over-transmitted in trios (TDTp = 0.001). Fut2 is transiently upregulated inmouse middle ear after inoculation withnon-typeable Haemophilus influenzae. Four FUT2 variants-namely p. Ala104Val, p. Arg138Cys, p. Trp154*, and p. Arg202*-reduced A antigen in mutant-transfected COS-7 cells, while the nonsense variants also reduced FUT2 protein levels. Common and rare FUT2 variants confer susceptibility to otitis media, likely by modifying the middle ear microbiome through regulation of A antigen levels in epithelial cells. Our familiesdemonstratemarked intra-familial genetic heterogeneity, suggesting thatmultiple combinations of common and rare variants plus environmental factors influence the individual otitis media phenotype as a complex trait.
  • Million Vet Program (2018)
    High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
  • Vesterinen, Tiina; Salmenkivi, Kaisa; Mustonen, Harri; Kuopio, Teijo; Lappi-Blanco, Elisa; Paavonen, Timo; Vainio, Paula; Knuuttila, Aija; Carpén, Olli; Haglund, Caj; Arola, Johanna (2020)
    Finnish hospital-integrated biobanks administer millions of formalin-fixed paraffin-embedded tissue samples collected within the clinical diagnostics. According to the Finnish Biobank Act, these samples can be coupled with patients’ clinical follow-up data and the data retrieved from national health registries. We collected a nationwide pulmonary carcinoid tumour series from Finnish biobanks to study prognostic factors as well as to explore how the number of tumours found in the Finnish biobanks corresponds to the number of tumours registered by the Finnish Cancer Registry (FCR). Finnish biobanks identified 88% of the tumours registered by the FCR and were able to deliver 63%. The main reasons for lacking samples were paucity of resected primary tumour tissue, incompatible primary diagnosis, and the absence of tissue blocks in the archives. The main bottleneck in the sample application process was retrieving patient data. Altogether, we received 224 tumour samples with appropriate patient data and identified six prognostic factors for shorter disease-specific survival: age over 56 years at the time of diagnosis, tumour size over 2.5 cm, atypical histology, Ki-67 proliferation index higher than 2.5%, hilar/mediastinal lymph node involvement at the time of diagnosis, and the presence of metastatic disease. In conclusion, the Finnish biobank infrastructure offers excellent opportunities for tissue-based research. However, to be able to develop the biobank operations further, involving more medical knowledge in the sample and data acquisition process is a necessity. Also, when working with tissue samples collected over decades, histological expertise is essential for re-evaluation and re-classification of the samples.
  • Service, Susan K.; Teslovich, Tanya M.; Fuchsberger, Christian; Ramensky, Vasily; Yajnik, Pranav; Koboldt, Daniel C.; Larson, David E.; Zhang, Qunyuan; Lin, Ling; Welch, Ryan; Ding, Li; McLellan, Michael D.; O'Laughlin, Michele; Fronick, Catrina; Fulton, Lucinda L.; Magrini, Vincent; Swift, Amy; Elliott, Paul; Jarvelin, Marjo-Riitta; Kaakinen, Marika; McCarthy, Mark I.; Peltonen, Leena; Pouta, Anneli; Bonnycastle, Lori L.; Collins, Francis S.; Narisu, Narisu; Stringham, Heather M.; Tuomilehto, Jaakko; Ripatti, Samuli; Fulton, Robert S.; Sabatti, Chiara; Wilson, Richard K.; Boehnke, Michael; Freimer, Nelson B. (2014)
  • Ripatti, Pietari; Ramo, Joel T.; Soderlund, Sanni; Surakka, Ida; Matikainen, Niina; Pirinen, Matti; Pajukanta, Paivi; Sarin, Antti-Pekka; Service, Susan K.; Laurila, Pirkka-Pekka; Ehnholm, Christian; Salomaa, Veikko; Wilson, Richard K.; Palotie, Aarno; Freimer, Nelson B.; Taskinen, Marja-Riitta; Ripatti, Samuli (2016)
    Familial combined hyperlipidemia (FCH) is a complex and common familial dyslipidemia characterized by elevated total cholesterol and/or triglyceride levels with over five-fold risk of coronary heart disease. The genetic architecture and contribution of rare Mendelian and common variants to FCH susceptibility is unknown. In 53 Finnish FCH families, we genotyped and imputed nine million variants in 715 family members with DNA available. We studied the enrichment of variants previously implicated with monogenic dyslipidemias and/or lipid levels in the general population by comparing allele frequencies between the FCH families and population samples. We also constructed weighted polygenic scores using 212 lipid-associated SNPs and estimated the relative contributions of Mendelian variants and polygenic scores to the risk of FCH in the families. We identified, across the whole allele frequency spectrum, an enrichment of variants known to elevate, and a deficiency of variants known to lower LDL-C and/or TG levels among both probands and affected FCH individuals. The score based on TG associated SNPs was particularly high among affected individuals compared to non-affected family members. Out of 234 affected FCH individuals across the families, seven (3%) carried Mendelian variants and 83 (35%) showed high accumulation of either known LDL-C or TG elevating variants by having either polygenic score over the 90th percentile in the population. The positive predictive value of high score was much higher for affected FCH individuals than for similar sporadic cases in the population. FCH is highly polygenic, supporting the hypothesis that variants across the whole allele frequency spectrum contribute to this complex familial trait. Polygenic SNP panels improve identification of individuals affected with FCH, but their clinical utility remains to be defined.
  • Dunn, Cory D. (2021)
    Next-generation sequencing can quickly reveal genetic variation potentially linked to heritable disease. As databases encompassing human variation continue to expand, rare variants have been of high interest, since the frequency of a variant is expected to be low if the genetic change leads to a loss of fitness or fecundity. However, the use of variant frequency when seeking genomic changes linked to disease remains very challenging. Here, I explored the role of selection in controlling human variant frequency using the HelixMT database, which encompasses hundreds of thousands of mitochondrial DNA (mtDNA) samples. I found that a substantial number of synonymous substitutions, which have no effect on protein sequence, were never encountered in this large study, while many other synonymous changes are found at very low frequencies. Further analyses of human and mammalian mtDNA datasets indicate that the population frequency of synonymous variants is predominantly determined by mutational biases rather than by strong selection acting upon nucleotide choice. My work has important implications that extend to the interpretation of variant frequency for non-synonymous substitutions.
  • Lee, Kyung Min; Ranta, Pertti; Saarikivi, Jarmo; Kutnar, Lado; Vreš, Branko; Dzhus, Maxim; Mutanen, Marko; Kvist, Laura (2020)
    Species occupying habitats subjected to frequent natural and/or anthropogenic changes are a challenge for conservation management. We studied one such species, Viola uliginosa, an endangered perennial wetland species typically inhabiting sporadically flooded meadows alongside rivers/lakes. In order to estimate genomic diversity, population structure, and history, we sampled five sites in Finland, three in Estonia, and one each in Slovenia, Belarus, and Poland using genomic SNP data with double-digest restriction site-associated DNA sequencing (ddRAD-seq). We found monophyletic populations, high levels of inbreeding (mean population F-SNP = 0.407-0.945), low effective population sizes (N-e = 0.8-50.9), indications of past demographic expansion, and rare long-distance dispersal. Our results are important in implementing conservation strategies for V. uliginosa, which should include founding of seed banks, ex situ cultivations, and reintroductions with individuals of proper origin, combined with continuous population monitoring and habitat management.