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- Association of mitochondrial polymorphism m.709G>A with Behcet's diseasePublication . Xavier, J. M.; Shafiee, N. M.; Ghaderi, F.; Rosa, A.; Abdollahi, B. S.; Nadji, A.; Shahram, F.; Davatchi, F.; Oliveira, S. A.
- Toward male individualization with rapidly mutating y‐chromosomal short tandem repeatsPublication . Ballantyne, Kaye N.; Ralf, Arwin; Aboukhalid, Rachid; Achakzai, Niaz M.; Anjos, Maria J.; Ayub, Qasim; Balažic, Jože; Ballantyne, Jack; Ballard, David J.; Berger, Burkhard; Bobillo, Cecilia; Bouabdellah, Mehdi; Burri, Helen; Capal, Tomas; Caratti, Stefano; Cárdenas, Jorge; Cartault, François; Carvalho, Elizeu F.; Carvalho, Monica; Cheng, Baowen; Coble, Michael D.; Comas, David; Corach, Daniel; D'Amato, Maria E.; Davison, Sean; de Knijff, Peter; De Ungria, Maria Corazon A.; Decorte, Ronny; Dobosz, Tadeusz; Dupuy, Berit M.; Elmrghni, Samir; Gliwiński, Mateusz; Gomes, Sara C.; Grol, Laurens; Haas, Cordula; Hanson, Erin; Henke, Jürgen; Henke, Lotte; Herrera-Rodríguez, Fabiola; Hill, Carolyn R.; Holmlund, Gunilla; Honda, Katsuya; Immel, Uta-Dorothee; Inokuchi, Shota; Jobling, Mark A.; Kaddura, Mahmoud; Kim, Jong S.; Kim, Soon H.; Kim, Wook; King, Turi E.; Klausriegler, Eva; Kling, Daniel; Kovačević, Lejla; Kovatsi, Leda; Krajewski, Paweł; Kravchenko, Sergey; Larmuseau, Maarten H. D.; Lee, Eun Young; Lessig, Ruediger; Livshits, Ludmila A.; Marjanović, Damir; Minarik, Marek; Mizuno, Natsuko; Moreira, Helena; Morling, Niels; Mukherjee, Meeta; Munier, Patrick; Nagaraju, Javaregowda; Neuhuber, Franz; Nie, Shengjie; Nilasitsataporn, Premlaphat; Nishi, Takeki; Oh, Hye H.; Olofsson, Jill; Onofri, Valerio; Palo, Jukka U.; Pamjav, Horolma; Parson, Walther; Petlach, Michal; Phillips, Christopher; Ploski, Rafal; Prasad, Samayamantri P. R.; Primorac, Dragan; Purnomo, Gludhug A.; Purps, Josephine; Rangel-Villalobos, Hector; Rębała, Krzysztof; Rerkamnuaychoke, Budsaba; Gonzalez, Danel Rey; Robino, Carlo; Roewer, Lutz; Rosa, Alexandra; Sajantila, Antti; Sala, Andrea; Salvador, Jazelyn M.; Sanz, Paula; Schmitt, Cornelia; Sharma, Anil K.; Silva, Dayse A.; Shin, Kyoung-Jin; Sijen, Titia; Sirker, Miriam; Siváková, Daniela; Škaro, Vedrana; Solano-Matamoros, Carlos; Souto, Luis; Stenzl, Vlastimil; Sudoyo, Herawati; Syndercombe-Court, Denise; Tagliabracci, Adriano; Taylor, Duncan; Tillmar, Andreas; Tsybovsky, Iosif S.; Tyler-Smith, Chris; van der Gaag, Kristiaan J.; Vanek, Daniel; Völgyi, Antónia; Ward, Denise; Willemse, Patricia; Yap, Eric P.H.; Yong, Rita Y.Y.; Pajnič, Irena Zupanič; Kayser, ManfredRelevant for various areas of human genetics, Y-chromosomal short tandem repeats (Y-STRs) are com monly used for testing close paternal relationships among individuals and populations, and for male lineage iden tification. However, even the widely used 17-loci Yfiler set cannot resolve individuals and populations completely. Here, 52 centers generated quality-controlled data of 13 rapidly mutating (RM) Y-STRs in 14,644 related and unrelated males from 111 worldwide populations. Strik ingly, >99% of the 12,272 unrelated males were com pletely individualized. Haplotype diversity was extremely high (global: 0.9999985, regional: 0.99836–0.9999988). Haplotype sharing between populations was almost ab sent except for six (0.05%) of the 12,156 haplotypes. Haplotype sharing within populations was generally rare (0.8% nonunique haplotypes), significantly lower in ur ban (0.9%) than rural (2.1%) and highest in endogamous groups (14.3%). Analysis of molecular variance revealed 99.98% of variation within populations, 0.018% among populations within groups, and 0.002% among groups. Of the 2,372 newly and 156 previously typed male relative pairs, 29% were differentiated including 27% of the 2,378 father–son pairs. Relative to Yfiler, haplotype diversity was increased in 86% of the populations tested and over all male relative differentiation was raised by 23.5%. Our study demonstrates the value of RM Y-STRs in identifying and separating unrelated and related males and provides a reference database.
- Asthma: snapshot or motion picture?Publication . Brehm, António; Rosa, Alexandra; Berenguer, Anabela G.
- African human mtDNA phylogeography at-a-glancePublication . Rosa, Alexandra; Brehm, AntónioThe mitochondrial DNA (mtDNA) genetic system has long proven to be useful for studying the demographic history of our species, since their proposed Southeast/East African origin 200 kya. Despite the weak archaeological and anthropologic records, which render a difficult understanding of early intra continental migrations, the phylogenetic L0-L1’6 split at about 140-160 kya is thought to represent also an early sub-structuring of small and isolated communities in South and East Africa. Regional variation accumulated over the following millennia, with L2 and L3 lineages arising in Central and East Africa 100-75 kya. Their sub-Saharan dispersal not later than 60 kya, largely overwhelmed the L0’1 distribution, nowadays limited to South African Khoisan and Central African Pygmies. Cyclic expansions and retractions of the equatorial forest between 40 kya and the “Last Glacial Aridity Maximum” were able to reduce the genetic diversity of modern humans.. Surviving regional-specific lineages have emerged from the Sahelian refuge areas, repopulating the region and contributing to the overall West African genetic similarity. Particular L1- L3 lineages mirror the substantial population growth made possible by moister and warmer conditions of the Sahara’s Wet Phase and the adoption of agriculture and iron smelting techniques. The diffusion of the farming expertise from a Central African source towards South Africa was mediated by the Bantu people 3 kya. The strong impact of their gene flow almost erased the pre-existent maternal pool. Non-L mtDNAs testify for Eurasian lineages that have enriched the African maternal pool at different timeframes: i) Near and Middle Eastern influences in Upper Palaeolithic, probably link to the spread of Afro-Asiatic languages; ii) particular lineages from West Eurasia around or after the glacial period; iii) post-glacial mtDNA signatures from the Franco-Cantabrian refugia, that have crossed the Strait of Gibraltar and iv) Eurasian lineages tracing back to the Neolithic or more recent historical episodes. Finally, the non-random sub-Saharan spread of North African lineages was likely mediated by the ancestors of Fulani, nomadic pastoral communities in the Sahel.
- Mitochondrial genome association study with peripheral arterial disease and venous thromboembolismPublication . Abrantes, Patrícia; Rosa, Alexandra; Francisco, Vânia; Sousa, Inês; Xavier, Joana M.; Oliveira, Sofia A.Background and aims: Peripheral arterial disease (PAD) and venous thromboembolism (VTE) are vascular traits sharing common modifiable and non-modifiable risk factors. These vascular pathologies have known nuclear-encoded genetic risk factors and the mitochondrial DNA may account for part of the missing heritability. To determine if PAD and VTE have a dual genetic control (mitochondrial and nu clear), we hereby investigated the association of mitochondrial DNA polymorphisms and haplogroups with these vascular traits. Methods: The association of mitochondrial single nucleotide polymorphisms (mtSNPs) and haplogroups was tested in 1652 PAD cases and 1629 controls from the eMERGE PAD genome-wide association study (GWAS), and 1241 VTE cases and 1278 controls from the GENEVA GWAS of venous thrombosis (dbGaP accession numbers phs000203.v1.p1 and phs000289.v2.p1, respectively). Results: 66 and 72 mtSNPs passed quality control filters and were tested for association with PAD and VTE, respectively. Significant evidence of population stratification could not be detected in both datasets. Three mtSNPs (m.477T > C, m.9667A > G, and m.10915T > C) were nominally associated (3.01 10 3 pa 3.96 10 2 ) with PAD in the logistic regression adjusted for confounding factors, and m.11914G > A was nominally associated (pa ¼ 4.14 10 2 ) with VTE. None of the nine major mito chondrial haplogroups were associated with either PAD or VTE. Conclusion: Unlike other vascular diseases such as stroke and diabetes, these results suggest that com mon mitochondrial variants individually or in combination do not play a major role in PAD and VTE susceptibility.
- Ulcerative colitis is under dual (mitochondrial and nuclear) genetic controlPublication . Rosa, Alexandra; Abrantes, Patrícia; Sousa, Inês; Francisco, Vânia; Santos, Patrícia; Francisco, David; Xavier, Joana M.; Oliveira, Sofia A.Background: Cellular oxidative stress and genetic susceptibility have been implicated in the multifactorial etiology of ulcerative colitis (UC). The nuclear genome association with UC has been intensely investigated, but the role of the mitochondrial DNA (mtDNA) has received far less attention and may account for part of the missing heritability. This study is a comprehensive analysis of the mtDNA contribution to UC susceptibility. Methods: The association of mitochondrial single-nucleotide polymorphisms (mtSNPs) and haplogroups with UC was tested in 488 cases and 833 controls of European ancestry from the NIDDK IBD Genetics Consortium Ulcerative Colitis Genome-Wide Association Study available through dbGaP and from the Illumina Genotype Control Database (studies 64 and 65). Results: No evidence of population stratification could be detected using 218 ancestry informative markers for European Americans. Seven of the 58 tested mtSNPs were nominally associated with UC, and A10550G in MT-ND4L withstands the Bonferroni correction (P ¼ 1.29E-06, odds ratio [ORG] [95% confidence interval (CI)] ¼ 4.80 [2.54–9.05], 10550G allele: 8.1% of patients and 1.9% of controls). A10550G remains equally associated after conditional analyses on the 11 UC genome-wide association studies (GWAS) top SNPs (6.35E-07 , Pcond , 4.58E-06), which suggests that it constitutes an independent risk factor from nuclear-encoded susceptibility loci. We detected additive (but not multiplicative) epistatic interactions between A10550G and all 11 top GWAS hits. Subhaplogroup K1 (P ¼ 0.021, OR [95% CI] ¼ 1.71 [1.08–2.69]) increased the risk for UC, whereas the U5b lineage conferred protection (P ¼ 0.016, OR [95% CI] ¼ 0.34 [0.14–0.82]). Conclusions: These results suggest that UC has a dual mitochondrial and nuclear genetic control that warrants further replication in independent data sets and reinforces its etiopathogenic complexity.
- Genetic polymorphisms and asthma: findings from a case–control study in the Madeira island populationPublication . Berenguer, Anabela; Fernandes, Ana; Oliveira, Susana; Rodrigues, Mariana; Ornelas, Pedro; Romeira, Diogo; Serrão, Tânia; Rosa, Alexandra; Câmara, RitaBackground: Asthma is a complex disease influenced by multiple genetic and environmental factors. While Madeira has the highest prevalence of asthma in Portugal (14.6%), the effect of both genetic and environmental factors in this population has never been assessed. We categorized 98 asthma patients according to the Global Initiative for Asthma (GINA) guidelines, established their sensitization profile, and measured their forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) indexes. Selected single nucleotide polymorphisms (SNPs) were analysed as potential markers for asthma susceptibility and severity in the interleukin 4 (IL4), interleukin 13 (IL13), beta-2-adrenergic receptor (ADRB2), a disintegrin and metalloprotease 33 (ADAM33), gasdermin-like (GSDML) and the signal transducer and activator of transcription 6 (STAT6) genes comparatively to a population reference set. Results: Although mites are the major source of allergic sensitization, no significant difference was found amongst asthma severity categories. IL4-590*CT/TT and IL4-RP2*253183/183183 were found to predict the risk (2-fold) and severity (3 to 4-fold) of asthma and were associated with a lower FEV1 index. ADRB2-c.16*AG is a risk factor (3.5-fold), while genotype GSDML-236*TT was protective (4-fold) for moderate-severe asthma. ADAM33-V4*C was associated to asthma and mild asthma by the transmission disequilibrium test (TDT). Finally, ADAM33-V4*CC and STAT6-21*TT were associated with higher sensitization (mean wheal size ≥10 mm) to house dust (1.4-fold) and storage mite (7.8-fold). Conclusion: In Madeira, IL4-590C/T, IL4-RP2 253/183, GSDML-236C/T and ADAM33-V4C/G SNPs are important risk factors for asthma susceptibility and severity, with implications for asthma healthcare management.
- Convergence of miRNA expression profiling, α-synuclein interacton and GWAS in Parkinson's diseasePublication . Martins, Madalena; Rosa, Alexandra; Guedes, Leonor C.; Fonseca, Benedita V.; Gotovac, Kristina; Violante, Sara; Mestre, Tiago; Coelho, Miguel; Rosa, Mário M.; Martin, Eden R.; Vance, Jeffery M.; Outeiro, Tiago F.; Wang, Liyong; Borovecki, Fran; Ferreira, Joaquim J.; Oliveira, Sofia A.miRNAs were recently implicated in the pathogenesis of numerous diseases, including neurological disorders such as Parkinson’s disease (PD). miRNAs are abundant in the nervous system, essential for efficient brain function and play important roles in neuronal patterning and cell specification. To further investigate their involvement in the etiology of PD, we conducted miRNA expression profiling in peripheral blood mononuclear cells (PBMCs) of 19 patients and 13 controls using microarrays. We found 18 miRNAs differentially expressed, and pathway analysis of 662 predicted target genes of 11 of these miRNAs revealed an over-representation in pathways previously linked to PD as well as novel pathways. To narrow down the genes for further investigations, we undertook a parallel approach using chromatin immunoprecipitation-sequencing (ChIP-seq) analysis to uncover genome-wide interactions of a-synuclein, a molecule with a central role in both monogenic and idiopathic PD. Convergence of ChIP-seq and miRNomics data highlighted the glycosphingolipid biosynthesis and the ubiquitin proteasome system as key players in PD. We then tested the association of target genes belonging to these pathways with PD risk, and identified nine SNPs in USP37 consistently associated with PD susceptibility in three genome-wide association studies (GWAS) datasets (0.46#OR#0.63) and highly significant in the meta-dataset (3.3661024 ,p,1.9461023 ). A SNP in ST8SIA4 was also highly associated with PD (p = 6.1561023 ) in the meta-dataset. These findings suggest that several miRNAs may act as regulators of both known and novel biological processes leading to idiopathic PD.