Browsing by Subject "GENETIC ARCHITECTURE"

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  • Varadharajan, Srinidhi; Rastas, Pasi; Löytynoja, Ari; Matschiner, Michael; Calboli, Federico C. F.; Guo, Baocheng; Nederbragt, Alexander J.; Jakobsen, Kjetill S.; Merilä, Juha (2019)
    The Gasterosteidae fish family hosts several species that are important models for eco-evolutionary, genetic, and genomic research. In particular, a wealth of genetic and genomic data has been generated for the three-spined stickleback (Gasterosteus aculeatus), the "ecology's supermodel," whereas the genomic resources for the nine-spined stickleback (Pungitius pungitius) have remained relatively scarce. Here, we report a high-quality chromosome-level genome assembly of P. pungitius consisting of 5,303 contigs (N50 = 1.2Mbp) with a total size of 521 Mbp. These contigs were mapped to 21 linkage groups using a high-density linkage map, yielding a final assembly with 98.5% BUSCO completeness. A total of 25,062 protein-coding genes were annotated, and about 23% of the assembly was found to consist of repetitive elements. A comprehensive analysis of repetitive elements uncovered centromere-specific tandem repeats and provided insights into the evolution of retrotransposons. A multigene phylogenetic analysis inferred a divergence time of about 26 million years ago (Ma) between nine- and three-spined sticklebacks, which is far older than the commonly assumed estimate of 13 Ma. Compared with the three-spined stickleback, we identified an additional duplication of several genes in the hemoglobin cluster. Sequencing data from populations adapted to different environments indicated potential copy number variations in hemoglobin genes. Furthermore, genome-wide synteny comparisons between three- and nine-spined sticklebacks identified chromosomal rearrangements underlying the karyotypic differences between the two species. The high-quality chromosome-scale assembly of the nine-spined stickleback genome obtained with long-read sequencing technology provides a crucial resource for comparative and population genomic investigations of stickleback fishes and teleosts.
  • Guo, Baocheng; Fang, Bohao; Shikano, Takahito; Momigliano, Paolo; Wang, Cui; Kravchenko, Alexandra; Merilä, Juha (2019)
    Hybridization and convergent evolution are phenomena of broad interest in evolutionary biology, but their occurrence poses challenges for reconstructing evolutionary affinities among affected taxa. Sticklebacks in the genus Pungitius are a case in point: evolutionary relationships and taxonomic validity of different species and populations in this circumpolarly distributed species complex remain contentious due to convergent evolution of traits regarded as diagnostic in their taxonomy, and possibly also due to frequent hybridization among taxa. To clarify the evolutionary relationships among different Pungitius species and populations globally, as well as to study the prevalence and extent of introgression among recognized species, genomic data sets of both reference genome-anchored single nucleotide polymorphisms and de novo assembled RAD-tag loci were constructed with RAD-seq data. Both data sets yielded topologically identical and well-supported species trees. Incongruence between nuclear and mitochondrial DNA-based trees was found and suggested possibly frequent hybridization and mitogenome capture during the evolution of Pungitius sticklebacks. Further analyses revealed evidence for frequent nuclear genetic introgression among Pungitius species, although the estimated proportions of autosomal introgression were low. Apart from providing evidence for frequent hybridization, the results challenge earlier mitochondrial and morphology-based hypotheses regarding the number of species and their affinities in this genus: at least seven extant species can be recognized on the basis of genetic data. The results also shed new light on the biogeographical history of the Pungitius-complex, including suggestion of several trans-Arctic invasions of Europe from the Northern Pacific. The well-resolved phylogeny should facilitate the utility of this genus as a model system for future comparative evolutionary studies.
  • Kemppainen, Petri; Husby, Arild (2018)
    A fundamental assumption in quantitative genetics is that traits are controlled by many loci of small effect. Using genomic data, this assumption can be tested using chromosome partitioning analyses, where the proportion of genetic variance for a trait explained by each chromosome (h(c)(2)), is regressed on its size. However, as h(c)(2)-estimates are necessarily positive (censoring) and the variance increases with chromosome size (heteroscedasticity), two fundamental assumptions of ordinary least squares (OLS) regression are violated. Using simulated and empirical data we demonstrate that these violations lead to incorrect inference of genetic architecture. The degree of bias depends mainly on the number of chromosomes and their size distribution and is therefore specific to the species; using published data across many different species we estimate that not accounting for this effect overall resulted in 28% false positives. We introduce a new and computationally efficient resampling method that corrects for inflation caused by heteroscedasticity and censoring and that works under a large range of dataset sizes and genetic architectures in empirical datasets. Our new method substantially improves the robustness of inferences from chromosome partitioning analyses.
  • Chan, Yingleong; Lim, Elaine T.; Sandholm, Niina; Wang, Sophie R.; McKnight, Amy Jayne; Ripke, Stephan; Daly, Mark J.; Neale, Benjamin M.; Salem, Rany M.; Hirschhorn, Joel N.; DIAGRAM Consortium; GENIE Consortium; GIANT Consortium; IIBDGC Consortium; PGC Consortium (2014)
  • Hu, Ming; Cebola, Ines; Carrat, Gaelle; Jiang, Shuying; Nawaz, Sameena; Khamis, Amna; Canouil, Mickael; Froguel, Philippe; Schulte, Anke; Solimena, Michele; Ibberson, Mark; Marchetti, Piero; Cardenas-Diaz, Fabian L.; Gadue, Paul J.; Hastoy, Benoit; Almeida-Souza, Leonardo; McMahon, Harvey; Rutter, Guy A. (2021)
    Using chromatin conformation capture, we show that an enhancer cluster in the STARD10 type 2 diabetes (T2D) locus forms a defined 3-dimensional (3D) chromatin domain. A 4.1-kb region within this locus, carrying 5 T2D-associated variants, physically interacts with CTCF-binding regions and with an enhancer possessing strong transcriptional activity. Analysis of human islet 3D chromatin interaction maps identifies the FCHSD2 gene as an additional target of the enhancer cluster. CRISPR-Cas9-mediated deletion of the variant region, or of the associated enhancer, from human pancreas-derived EndoC-bH1 cells impairs glucose- stimulated insulin secretion. Expression of both STARD10 and FCHSD2 is reduced in cells harboring CRISPR deletions, and lower expression of STARD10 and FCHSD2 is associated, the latter nominally, with the possession of risk variant alleles in human islets. Finally, CRISPR-Cas9-mediated loss of STARD10 or FCHSD2, but not ARAP1, impairs regulated insulin secretion. Thus, multiple genes at the STARD10 locus influence b cell function.
  • UK IBD Genetics Consortium; Natl Inst Diabet Digestive Kidney; Gettler, Kyle; Levantovsky, Rachel; Moscati, Arden; Daly, Mark J.; Cho, Judy H. (2021)
    BACKGROUND AND AIMS: Polygenic risk scores (PRS) may soon be used to predict inflammatory bowel disease (IBD) risk in prevention efforts. We leveraged exome-sequence and single nucleotide polymorphism (SNP) array data from 29,358 individuals in the multiethnic, randomly ascertained health system-based BioMe biobank to define effects of common and rare IBD variants on disease prediction and pathophysiology. METHODS: PRS were calculated from European, African American, and Ashkenazi Jewish (AJ) reference case-control studies, and a meta-GWAS run using all three association datasets. PRS were then combined using regression to assess which combination of scores best predicted IBD status in European, AJ, Hispanic, and African American cohorts in BioMe. Additionally, rare variants were assessed in genes associated with very early-onset IBD (VEO-IBD), by estimating genetic penetrance in each BioMe population. RESULTS: Combining risk scores based on association data from distinct ancestral populations improved IBD prediction for every population in BioMe and significantly improved prediction among European ancestry UK Biobank individuals. Lower predictive power for non-Europeans was observed, reflecting in part substantially lower African IBD case-control reference sizes. We replicated associations for two VEO-IBD genes, ADAM17 and LRBA, with high dominant model penetrance in BioMe. Autosomal recessive LRBA risk alleles are associated with severe, early-onset autoimmunity; we show that heterozygous carriage of an African-predominant LRBA protein-altering allele is associated with significantly decreased LRBA and CTLA-4 expression with T-cell activation. CONCLUSIONS: Greater genetic diversity in African populations improves prediction across populations, and generalizes some VEO-IBD genes. Increasing African American IBD case-collections should be prioritized to reduce health disparities and enhance pathophysiological insight.
  • Rastas, Pasi; Calboli, Federico C. F.; Guo, Baocheng; Shikano, Takahito; Merilä, Juha (2016)
    High-density linkage maps are important tools for genome biology and evolutionary genetics by quantifying the extent of recombination, linkage disequilibrium, and chromosomal rearrangements across chromosomes, sexes, and populations. They provide one of the best ways to validate and refine de novo genome assemblies, with the power to identity errors in assemblies increasing with marker density. However, assembly of high-density linkage maps is still challenging due to software limitations. We describe Lep-MAP2, a software for ultradense genome-wide linkage map construction. Lep-MAP2 can handle various family structures and can account for achiasmatic meiosis to gain linkage map accuracy. Simulations show that Lep-MAP2 outperforms other available mapping software both in computational efficiency and accuracy. When applied to two large F-2-generation recombinant crosses between two nine-spined stickleback (Pungitius pungitius) populations, it produced two high-density (similar to 6 markers/cM) linkage maps containing 18,691 and 20,054 single nucleotide polymorphisms. The two maps showed a high degree of synteny, but female maps were 1.5-2 times longer than male maps in all linkage groups, suggesting genome-wide recombination suppression in males. Comparison with the genome sequence of the three-spined stickleback (Gasterosteus aculeatus) revealed a high degree of interspecific synteny with a low frequency (
  • Flannick, Jason; Fuchsberger, Christian; Mahajan, Anubha; Teslovich, Tanya M.; Agarwala, Vineeta; Gaulton, Kyle J.; Caulkins, Lizz; Koesterer, Ryan; Ma, Clement; Moutsianas, Loukas; McCarthy, Davis J.; Rivas, Manuel A.; Perry, John R. B.; Sim, Xueling; Blackwell, Thomas W.; Robertson, Neil R.; Rayner, N. William; Cingolani, Pablo; Locke, Adam E.; Tajes, Juan Fernandez; Highland, Heather M.; Dupuis, Josee; Chines, Peter S.; Lindgren, Cecilia M.; Hartl, Christopher; Jackson, Anne U.; Chen, Han; Huyghe, Jeroen R.; De Bunt, Martijn Van; Pearson, Richard D.; Kumar, Ashish; Muller-Nurasyid, Martina; Grarup, Niels; Stringham, Heather M.; Gamazon, Eric R.; Lee, Jaehoon; Chen, Yuhui; Scott, Robert A.; Below, Jennifer E.; Chen, Peng; Huang, Jinyan; Go, Min Jin; Stitzel, Michael L.; Pasko, Dorota; Parker, Stephen C. J.; Varga, Tibor V.; Green, Todd; Beer, Nicola L.; Day-Williams, Aaron G.; Ferreira, Teresa; Fingerlin, Tasha; Horikoshi, Momoko; Hu, Cheng; Huh, Iksoo; Ikram, Mohammad Kamran; Kim, Bong-Jo; Kim, Yongkang; Kim, Young Jin; Kwon, Min-Seok; Lee, Juyoung; Lee, Selyeong; Lin, Keng-Han; Maxwell, Taylor J.; Nagai, Yoshihiko; Wang, Xu; Welch, Ryan P.; Yoon, Joon; Zhang, Weihua; Barzilai, Nir; Voight, Benjamin F.; Han, Bok-Ghee; Jenkinson, Christopher P.; Kuulasmaa, Teemu; Kuusisto, Johanna; Manning, Alisa; Ng, Maggie C. Y.; Palmer, Nicholette D.; Balkau, Beverley; Stancakova, Alena; Abboud, Hanna E.; Boeing, Heiner; Giedraitis, Vilmantas; Prabhakaran, Dorairaj; Gottesman, Omri; Scott, James; Carey, Jason; Kwan, Phoenix; Grant, George; Smith, Joshua D.; Neale, Benjamin M.; Purcell, Shaun; Butterworth, Adam S.; Howson, Joanna M. M.; Lee, Heung Man; Lu, Yingchang; Kwak, Soo-Heon; Zhao, Wei; Danesh, John; Lam, Vincent K. L.; Park, Kyong Soo; Saleheen, Danish; So, Wing Yee; Tam, Claudia H. T.; Afzal, Uzma; Aguilar, David; Arya, Rector; Aung, Tin; Chan, Edmund; Navarro, Carmen; Cheng, Ching-Yu; Palli, Domenico; Correa, Adolfo; Curran, Joanne E.; Rybin, Dennis; Farook, Vidya S.; Fowler, Sharon P.; Freedman, Barry I.; Griswold, Michael; Hale, Daniel Esten; Hicks, Pamela J.; Khor, Chiea-Chuen; Kumar, Satish; Lehne, Benjamin; Thuillier, Dorothee; Lim, Wei Yen; Liu, Jianjun; Loh, Marie; Musani, Solomon K.; Puppala, Sobha; Scott, William R.; Yengo, Loic; Tan, Sian-Tsung; Taylor, Herman A.; Thameem, Farook; Wilson, Gregory; Wong, Tien Yin; Njolstad, Pal Rasmus; Levy, Jonathan C.; Mangino, Massimo; Bonnycastle, Lori L.; Schwarzmayr, Thomas; Fadista, Joao; Surdulescu, Gabriela L.; Herder, Christian; Groves, Christopher J.; Wieland, Thomas; Bork-Jensen, Jette; Brandslund, Ivan; Christensen, Cramer; Koistinen, Heikki A.; Doney, Alex S. F.; Kinnunen, Leena; Esko, Tonu; Farmer, Andrew J.; Hakaste, Liisa; Hodgkiss, Dylan; Kravic, Jasmina; Lyssenko, Valeriya; Hollensted, Mette; Jorgensen, Marit E.; Jorgensen, Torben; Ladenvall, Claes; Justesen, Johanne Marie; Karajamaki, Annemari; Kriebel, Jennifer; Rathmann, Wolfgang; Lannfelt, Lars; Lauritzen, Torsten; Narisu, Narisu; Linneberg, Allan; Melander, Olle; Milani, Lili; Neville, Matt; Orho-Melander, Marju; Qi, Lu; Qi, Qibin; Roden, Michael; Rolandsson, Olov; Swift, Amy; Rosengren, Anders H.; Stirrups, Kathleen; Wood, Andrew R.; Mihailov, Evelin; Blancher, Christine; Carneiro, Mauricio O.; Maguire, Jared; Poplin, Ryan; Shakir, Khalid; Fennell, Timothy; DePristo, Mark; De Angelis, Martin Hrabe; Deloukas, Panos; Gjesing, Anette P.; Jun, Goo; Nilsson, Peter M.; Murphy, Jacquelyn; Onofrio, Robert; Thorand, Barbara; Hansen, Torben; Meisinger, Christa; Hu, Frank B.; Isomaa, Bo; Karpe, Fredrik; Liang, Liming; Peters, Annette; Huth, Cornelia; O'Rahilly, Stephen P.; Palmer, Colin N. A.; Pedersen, Oluf; Rauramaa, Rainer; Tuomilehto, Jaakko; Salomaa, Veikko; Watanabe, Richard M.; Syvanen, Ann-Christine; Bergman, Richard N.; Bharadwaj, Dwaipayan; Bottinger, Erwin P.; Cho, Yoon Shin; Chandak, Giriraj R.; Chan, Juliana Cn; Chia, Kee Seng; Daly, Mark J.; Ebrahim, Shah B.; Langenberg, Claudia; Elliott, Paul; Jablonski, Kathleen A.; Lehman, Donna M.; Jia, Weiping; Ma, Ronald Cw; Pollin, Toni I.; Sandhu, Manjinder; Tandon, Nikhil; Froguel, Philippe; Barroso, Ines; Teo, Yik Ying; Zeggini, Eleftheria; Loos, Ruth J. F.; Small, Kerrin S.; Ried, Janina S.; DeFronzo, Ralph A.; Grallert, Harald; Glaser, Benjamin; Metspalu, Andres; Wareham, Nicholas J.; Walker, Mark; Banks, Eric; Gieger, Christian; Ingelsson, Erik; Im, Hae Kyung; Illig, Thomas; Franks, Paul W.; Buck, Gemma; Trakalo, Joseph; Buck, David; Prokopenko, Inga; Magi, Reedik; Lind, Lars; Farjoun, Yossi; Owen, Katharine R.; Gloyn, Anna L.; Strauch, Konstantin; Tuomi, Tiinamaija; Kooner, Jaspal Singh; Lee, Jong-Young; Park, Taesung; Donnelly, Peter; Morris, Andrew D.; Hattersley, Andrew T.; Bowden, Donald W.; Collins, Francis S.; Atzmon, Gil; Chambers, John C.; Spector, Timothy D.; Laakso, Markku; Strom, Tim M.; Bell, Graeme I.; Blangero, John; Duggirala, Ravindranath; Tai, EShyong; McVean, Gilean; Hanis, Craig L.; Wilson, James G.; Seielstad, Mark; Frayling, Timothy M.; Meigs, James B.; Cox, Nancy J.; Sladek, Rob; Lander, Eric S.; Gabriel, Stacey; Mohlke, Karen L.; Meitinger, Thomas; Groop, Leif; Abecasis, Goncalo; Scott, Laura J.; Morris, Andrew P.; Kang, Hyun Min; Altshuler, David; Burtt, Noel P.; Florez, Jose C.; Boehnke, Michael; McCarthy, Mark I. (2017)
    To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (> 80% of low-frequency coding variants in similar to 82 K Europeans via the exome chip, and similar to 90% of low-frequency non-coding variants in similar to 44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
  • ADHD Working Grp Psychiat Genomics; Early Lifecourse Genetic; 23andMe Res Team; Daly, Mark J. (2019)
    Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.
  • Mahajan, Anubha; Taliun, Daniel; Thurner, Matthias; Robertson, Neil R.; Torres, Jason M.; Rayner, N. William; Payne, Anthony J.; Steinthorsdottir, Valgerdur; Scott, Robert A.; Grarup, Niels; Cook, James P.; Schmidt, Ellen M.; Wuttke, Matthias; Sarnowski, Chloe; Magill, Reedik; Nano, Jana; Gieger, Christian; Trompet, Stella; Lecoeur, Cecile; Preuss, Michael H.; Prins, Bram Peter; Guo, Xiuqing; Bielak, Lawrence F.; Below, Jennifer E.; Bowden, Donald W.; Chambers, John Campbell; Kim, Young Jin; Ng, Maggie C. Y.; Petty, Lauren E.; Sim, Xueling; Zhang, Weihua; Bennett, Amanda J.; Bork-Jensen, Jette; Brummett, Chad M.; Canouil, Mickael; Kardt, Kai-Uwe Ec; Fischer, Krista; Kardia, Sharon L. R.; Kronenberg, Florian; Lall, Kristi; Liu, Ching-Ti; Locke, Adam E.; Luan, Jian'an; Ntalla, Loanna; Nylander, Vibe; Schoenherr, Sebastian; Schurmann, Claudia; Yengo, Loic; Bottinger, Erwin P.; Brandslund, Ivan; Christensen, Cramer; Dedoussis, George; Florez, Jose C.; Ford, Ian; France, Oscar H.; Frayling, Timothy M.; Giedraitis, Vilmantas; Hackinger, Sophie; Hattersley, Andrew T.; Herder, Christian; Ikram, M. Arfan; Ingelsson, Martin; Jorgensen, Marit E.; Jorgensen, Torben; Kriebel, Jennifer; Kuusisto, Johanna; Ligthart, Symen; Lindgren, Cecilia M.; Linneberg, Allan; Lyssenko, Valeriya; Mamakou, Vasiliki; Meitinger, Thomas; Mohlke, Karen L.; Morris, Andrew D.; Nadkarni, Girish; Pankow, James S.; Peters, Annette; Sattar, Naveed; Stancakova, Alena; Strauch, Konstantin; Taylor, Kent D.; Thorand, Barbara; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Tuomilehto, Jaakko; Witte, Daniel R.; Dupuis, Josee; Peyser, Patricia A.; Zeggini, Eleftheria; Loos, Ruth J. F.; Froguel, Philippe; Ingelsson, Erik; Lind, Lars; Groop, Leif; Laakso, Markku; Collins, Francis S.; Jukema, J. Wouter; Palmer, Colin N. A.; Grallert, Harald; Metspalu, Andres; Dehghan, Abbas; Koettgen, Anna; Abecasis, Goncalo R.; Meigs, James B.; Rotter, Jerome; Marchini, Jonathan; Pedersen, Oluf; Hansen, Torben; Langenberg, Claudia; Wareham, Nicholas J.; Stefansson, Kari; Gloyn, Anna L.; Morris, Andrew P.; Boehnke, Michael; McCarthy, Mark (2018)
    We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci,135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency 2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).
  • Bone Mineral Density Childhood; Groop, Leif; Leslie, R. David; Gran, Struan F.A. (2018)
    OBJECTIVELatent autoimmune diabetes in adults (LADA) shares clinical features with both type 1 and type 2 diabetes; however, there is ongoing debate regarding the precise definition of LADA. Understanding its genetic basis is one potential strategy to gain insight into appropriate classification of this diabetes subtype.RESEARCH DESIGN AND METHODSWe performed the first genome-wide association study of LADA in case subjects of European ancestry versus population control subjects (n = 2,634 vs. 5,947) and compared against both case subjects with type 1 diabetes (n = 2,454 vs. 968) and type 2 diabetes (n = 2,779 vs. 10,396).RESULTSThe leading genetic signals were principally shared with type 1 diabetes, although we observed positive genetic correlations genome-wide with both type 1 and type 2 diabetes. Additionally, we observed a novel independent signal at the known type 1 diabetes locus harboring PFKFB3, encoding a regulator of glycolysis and insulin signaling in type 2 diabetes and inflammation and autophagy in autoimmune disease, as well as an attenuation of key type 1-associated HLA haplotype frequencies in LADA, suggesting that these are factors that distinguish childhood-onset type 1 diabetes from adult autoimmune diabetes.CONCLUSIONSOur results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies.
  • Deshmukh, Harshal A.; Madsen, Anne Lundager; Vinuela, Ana; Have, Christian Theil; Grarup, Niels; Tura, Andrea; Mahajan, Anubha; Heggie, Alison J.; Koivula, Robert W.; De Masi, Federico; Tsirigos, Konstantinos K.; Linneberg, Allan; Drivsholm, Thomas; Pedersen, Oluf; Sorensen, Thorkild I. A.; Astrup, Arne; Gjesing, Anette A. P.; Pavo, Imre; Wood, Andrew R.; Ruetten, Hartmut; Jones, Angus G.; Koopman, Anitra D. M.; Cederberg, Henna; Rutters, Femke; Ridderstrale, Martin; Laakso, Markku; McCarthy, Mark; Frayling, Tim M.; Ferrannini, Ele; Franks, Paul W.; Pearson, Ewan R.; Mari, Andrea; Hansen, Torben; Walker, Mark (2021)
    Context: Pancreatic beta-cell glucose sensitivity is the slope of the plasma glucose-insulin secretion relationship and is a key predictor of deteriorating glucose tolerance and development of type 2 diabetes. However, there are no large-scale studies looking at the genetic determinants of beta-cell glucose sensitivity. Objective: To understand the genetic determinants of pancreatic beta-cell glucose sensitivity using genome-wide meta-analysis and candidate gene studies. Design: We performed a genome-wide meta-analysis for beta-cell glucose sensitivity in subjects with type 2 diabetes and nondiabetic subjects from 6 independent cohorts (n = 5706). Beta-cell glucose sensitivity was calculated from mixed meal and oral glucose tolerance tests, and its associations between known glycemia-related single nucleotide polymorphisms (SNPs) and genome-wide association study (GWAS) SNPs were estimated using linear regression models. Results: Beta-cell glucose sensitivity was moderately heritable (h2 ranged from 34% to 55%) using SNP and family-based analyses. GWAS meta-analysis identified multiple correlated SNPs in the CDKAL1 gene and GIPR-QPCTL gene loci that reached genome-wide significance, with SNP rs2238691 in GIPR-QPCTL (P value = 2.64 x 10(-9)) and rs9368219 in the CDKAL1 (P value = 3.15 x 10(-9)) showing the strongest association with beta-cell glucose sensitivity. These loci surpassed genome-wide significance when the GWAS meta-analysis was repeated after exclusion of the diabetic subjects. After correction for multiple testing, glycemia-associated SNPs in or near the HHEX and IGF2B2 loci were also associated with beta-cell glucose sensitivity. Conclusion: We show that, variation at the GIPR-QPCTL and CDKAL1 loci are key determinants of pancreatic beta-cell glucose sensitivity.
  • Baison, John; Vidalis, Amaryllis; Zhou, Linghua; Chen, Zhi-Qiang; Li, Zitong; Sillanpää, Mikko J.; Bernhardsson, Carolina; Scofield, Douglas; Forsberg, Nils; Grahn, Thomas; Olsson, Lars; Karlsson, Bo; Wu, Harry; Ingvarsson, Pär K.; Lundqvist, Sven-Olof; Niittylae, Totte; Garcia-Gil, M. Rosario (2019)
    Norway spruce is a boreal forest tree species of significant ecological and economic importance. Hence there is a strong imperative to dissect the genetics underlying important wood quality traits in the species. We performed a functional genome-wide association study (GWAS) of 17 wood traits in Norway spruce using 178 101 single nucleotide polymorphisms (SNPs) generated from exome genotyping of 517 mother trees. The wood traits were defined using functional modelling of wood properties across annual growth rings. We applied a Least Absolute Shrinkage and Selection Operator (LASSO-based) association mapping method using a functional multilocus mapping approach that utilizes latent traits, with a stability selection probability method as the hypothesis testing approach to determine a significant quantitative trait locus. The analysis provided 52 significant SNPs from 39 candidate genes, including genes previously implicated in wood formation and tree growth in spruce and other species. Our study represents a multilocus GWAS for complex wood traits in Norway spruce. The results advance our understanding of the genetics influencing wood traits and identifies candidate genes for future functional studies.
  • Hebbar, Prashantha; Abu-Farha, Mohamed; Alkayal, Fadi; Nizam, Rasheeba; Elkum, Naser; Melhem, Motasem; John, Sumi Elsa; Channanath, Arshad; Abubaker, Jehad; Bennakhi, Abdullah; Al-Ozairi, Ebaa; Tuomilehto, Jaakko; Pitkäniemi, Janne; Alsmadi, Osama; Al-Mulla, Fahd; Thanaraj, Thangavel Alphonse (2020)
    Consanguineous populations of the Arabian Peninsula, which has seen an uncontrolled rise in type 2 diabetes incidence, are underrepresented in global studies on diabetes genetics. We performed a genome-wide association study on the quantitative trait of fasting plasma glucose (FPG) in unrelated Arab individuals from Kuwait (discovery-cohort:n = 1,353; replication-cohort:n = 1,196). Genome-wide genotyping in discovery phase was performed for 632,375 markers from Illumina HumanOmniExpress Beadchip; and top-associating markers were replicated using candidate genotyping. Genetic models based on additive and recessive transmission modes were used in statistical tests for associations in discovery phase, replication phase, and meta-analysis that combines data from both the phases. A genome-wide significant association with high FPG was found at rs1002487 (RPS6KA1) (p-discovery = 1.64E-08, p-replication = 3.71E-04, p-combined = 5.72E-11; beta-discovery = 8.315; beta-replication = 3.442; beta-combined = 6.551). Further, three suggestive associations (p-values <8.2E-06) with high FPG were observed at rs487321 (CADPS), rs707927 (VARS and 2Kb upstream of VWA7), and rs12600570 (DHX58); the first two markers reached genome-wide significance in the combined analysis (p-combined = 1.83E-12 and 3.07E-09, respectively). Significant interactions of diabetes traits (serum triglycerides, FPG, and glycated hemoglobin) with homeostatic model assessment of insulin resistance were identified for genotypes heterozygous or homozygous for the risk allele. Literature reports support the involvement of these gene loci in type 2 diabetes etiology.
  • Liu, Ching-Ti; Merino, Jordi; Rybin, Denis; DiCorpo, Daniel; Benke, Kelly S.; Bragg-Gresham, Jennifer L.; Canouil, Mickaël; Corre, Tanguy; Grallert, Harald; Isaacs, Aaron; Kutalik, Zoltan; Lahti, Jari; Marullo, Letizia; Marzi, Carola; Rasmussen-Torvik, Laura J.; Rocheleau, Ghislain; Rueedi, Rico; Scapoli, Chiara; Verweij, Niek; Vogelzangs, Nicole; Willems, Sara M.; Yengo, Loïc; Bakker, Stephan J. L.; Beilby, John; Hui, Jennie; Kajantie, Eero; Müller-Nurasyid, Martina; Rathmann, Wolfgang; Balkau, Beverley; Bergmann, Sven; Eriksson, Johan G.; Florez, Jose C.; Froguel, Philippe; Harris, Tamara; Hung, Joseph; James, Alan L.; Kavousi, Maryam; Miljkovic, Iva; Musk, Arthur W.; Palmer, Lyle J.; Peters, Annette; Roussel, Ronan; van der harst, Pim; van Duijn, Cornelia M.; Vollenweider, Peter; Barroso, Inês; Prokopenko, Inga; Dupuis, Josée; Meigs, James B.; Bouatia-Naji, Nabila (2019)
    Type 2 diabetes (T2D) affects the health of millions of people worldwide. The identification of genetic determinants associated with changes in glycemia over time might illuminate biological features that precede the development of T2D. Here we conducted a genome-wide association study of longitudinal fasting glucose changes in up to 13,807 non-diabetic individuals of European descent from nine cohorts. Fasting glucose change over time was defined as the slope of the line defined by multiple fasting glucose measurements obtained over up to 14 years of observation. We tested for associations of genetic variants with inverse-normal transformed fasting glucose change over time adjusting for age at baseline, sex, and principal components of genetic variation. We found no genome-wide significant association (P < 5 x 10(-8)) with fasting glucose change over time. Seven loci previously associated with T2D, fasting glucose or HbA1c were nominally (P < 0.05) associated with fasting glucose change over time. Limited power influences unambiguous interpretation, but these data suggest that genetic effects on fasting glucose change over time are likely to be small. A public version of the data provides a genomic resource to combine with future studies to evaluate shared genetic links with T2D and other metabolic risk traits.
  • Int League Against Epilepsy Conso; Abou-Khalil, Bassel; Eriksson, Johan G.; Lehesjoki, Anna-Elina; Palotie, Aarno (2018)
    The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.
  • Kerminen, Sini; Martin, Alicia R.; Koskela, Jukka; Ruotsalainen, Sanni E.; Havulinna, Aki S.; Surakka, Ida; Palotie, Aarno; Perola, Markus; Salomaa, Veikko; Daly, Mark J.; Ripatti, Samuli; Pirinen, Matti (2019)
    Polygenic scores (PSs) are becoming a useful tool to identify individuals with high genetic risk for complex diseases, and several projects are currently testing their utility for translational applications. It is also tempting to use PSs to assess whether genetic variation can explain a part of the geographic distribution of a phenotype. However, it is not well known how the population genetic properties of the training and target samples affect the geographic distribution of PSs. Here, we evaluate geographic differences, and related biases, of PSs in Finland in a geographically well-defined sample of 2,376 individuals from the National FINRISK study. First, we detect geographic differences in PSs for coronary artery disease (CAD), rheumatoid arthritis, schizophrenia, waist-hip ratio (WHR), body-mass index (BMI), and height, but not for Crohn disease or ulcerative colitis. Second, we use height as a model trait to thoroughly assess the possible population genetic biases in PSs and apply similar approaches to the other phenotypes. Most importantly, we detect suspiciously large accumulations of geographic differences for CAD, WHR, BMI, and height, suggesting bias arising from the population's genetic structure rather than from a direct genotype-phenotype association. This work demonstrates how sensitive the geographic patterns of current PSs are for small biases even within relatively homogeneous populations and provides simple tools to identify such biases. A thorough understanding of the effects of population genetic structure on PSs is essential for translational applications of PSs.
  • Bolotovskiy, Aleksey A.; Levina, Marina A.; DeFaveri, Jacquelin; Merila, Juha; Levin, Boris A. (2018)
    The three-spined stickleback Gasterosteus aculeatus is an important model for studying microevolution and parallel adaptation to freshwater environments. Marine and freshwater forms differ markedly in their phenotype, especially in the number of lateral plates, which are serially repeated elements of the exoskeleton. In fishes, thyroid hormones are involved in adaptation to salinity, as well as the developmental regulation of serially repeated elements. To study how thyroid hormones influence lateral plate development, we manipulated levels of triiodothyronine and thiourea during early ontogeny in a marine and freshwater population with complete and low plate phenotypes, respectively. The development of lateral plates along the body and keel was heterochronic among experimental groups. Fish with a low dosage of exogenous triiodothyronine and those treated with thiourea exhibited retarded development of bony plates compared to both control fish and those treated with higher a triiodothyronine dosage. Several triiodothyronine-treated individuals of the marine form expressed the partial lateral plate phenotype. Some individuals with delayed development of lateral plates manifested 1-2 extra bony plates located above the main row of lateral plates.
  • Trokovic, Nina; Herczeg, Gabor; Ab Ghani, Nurul Izza; Shikano, Takahito; Merila, Juha (2012)
    Background Fluctuating asymmetry (FA), defined as small random deviations from the ideal bilateral symmetry, has been hypothesized to increase in response to both genetic and environmental stress experienced by a population. We compared levels of FA in 12 bilateral meristic traits (viz. lateral-line system neuromasts and lateral plates), and heterozygosity in 23 microsatellite loci, among four marine (high piscine predation risk) and four pond (zero piscine predation risk) populations of nine-spined sticklebacks (Pungitius pungitius). Results Pond sticklebacks had on average three times higher levels of FA than marine fish and this difference was highly significant. Heterozygosity in microsatellite markers was on average two times lower in pond (HE ≈ 0.3) than in marine (HE ≈ 0.6) populations, and levels of FA and heterozygosity were negatively correlated across populations. However, after controlling for habitat effect on heterozygosity, levels of FA and heterozygosity were uncorrelated. Conclusions The fact that levels of FA in traits likely to be important in the context of predator evasion were elevated in ponds compared to marine populations suggests that relaxed selection for homeostasis in ponds lacking predatory fish may be responsible for the observed habitat difference in levels of FA. This inference also aligns with the observation that the levels of genetic variability across the populations did not explain population differences in levels of FA after correcting for habitat effect. Hence, while differences in strength of selection, rather than in the degree of genetic stress could be argued to explain habitat differences in levels of FA, the hypothesis that increased FA in ponds is caused by genetic stress cannot be rejected.
  • Mahajan, Anubha; Sim, Xueling; Ng, Hui Jin; Manning, Alisa; Rivas, Manuel A.; Highland, Heather M.; Locke, Adam E.; Grarup, Niels; Im, Hae Kyung; Cingolani, Pablo; Flannick, Jason; Fontanillas, Pierre; Fuchsberger, Christian; Gaulton, Kyle J.; Teslovich, Tanya M.; Rayner, N. William; Robertson, Neil R.; Beer, Nicola L.; Rundle, Jana K.; Bork-Jensen, Jette; Ladenvall, Claes; Blancher, Christine; Buck, David; Buck, Gemma; Burtt, Noel P.; Gabriel, Stacey; Gjesing, Anette P.; Groves, Christopher J.; Hollensted, Mette; Huyghe, Jeroen R.; Jackson, Anne U.; Jun, Goo; Justesen, Johanne Marie; Mangino, Massimo; Murphy, Jacquelyn; Neville, Matt; Onofrio, Robert; Small, Kerrin S.; Stringham, Heather M.; Syvanen, Ann-Christine; Trakalo, Joseph; Abecasis, Goncalo; Bell, Graeme I.; Blangero, John; Cox, Nancy J.; Duggirala, Ravindranath; Isomaa, Bo; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Groop, Leif; T2D-GENES Consortium; Go-T2D Consortium (2015)