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in category genetics
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5,665 downloads genetics
Farming was established in Central Europe by the Linearbandkeramik culture (LBK), a well-investigated archaeological horizon, which emerged in the Carpathian Basin, in today's Hungary. However, the genetic background of the LBK genesis has not been revealed yet. Here we present 9 Y chromosomal and 84 mitochondrial DNA profiles from Mesolithic, Neolithic Starčevo and LBK sites (7th/6th millennium BC) from the Carpathian Basin and south-eastern Europe. We detect genetic continuity of both maternal and paternal elements during the initial spread of agriculture, and confirm the substantial genetic impact of early farming south-eastern European and Carpathian Basin cultures on Central European populations of the 6th-4th millennium BC. Our comprehensive Y chromosomal and mitochondrial DNA population genetic analyses demonstrate a clear affinity of the early farmers to the modern Near East and Caucasus, tracing the expansion from that region through south-eastern Europe and the Carpathian Basin into Central Europe. Our results also reveal contrasting patterns for male and female genetic diversity in the European Neolithic, suggesting patrilineal descent system and patrilocal residential rules among the early farmers.
5,531 downloads genetics
Genome-wide association studies (GWAS) stand as powerful experimental designs for identifying DNA variants associated with complex traits and diseases. In the past decade, both the number of such studies and their sample sizes have increased dramatically. Recent GWAS of height and body mass index (BMI) in ~250,000 European participants have led to the discovery of ~700 and ~100 nearly independent SNPs associated with these traits, respectively. Here we combine summary statistics from those two studies with GWAS of height and BMI performed in ~450,000 UK Biobank participants of European ancestry. Overall, our combined GWAS meta-analysis reaches N~700,000 individuals and substantially increases the number of GWAS signals associated with these traits. We identified 3,290 and 716 near-independent SNPs associated with height and BMI, respectively (at a revised genome-wide significance threshold of p<10-8), including 1,185 height-associated SNPs and 554 BMI-associated SNPs located within loci not previously identified by these two GWAS. The genome-wide significant SNPs explain ~24.6% of the variance of height and ~5% of the variance of BMI in an independent sample from the Health and Retirement Study (HRS). Correlations between polygenic scores based upon these SNPs with actual height and BMI in HRS participants were 0.44 and 0.20, respectively. From analyses of integrating GWAS and eQTL data by Summary-data based Mendelian Randomization (SMR), we identified an enrichment of eQTLs amongst lead height and BMI signals, prioritisting 684 and 134 genes, respectively. Our study demonstrates that, as previously predicted, increasing GWAS sample sizes continues to deliver, by discovery of new loci, increasing prediction accuracy and providing additional data to achieve deeper insight into complex trait biology. All summary statistics are made available for follow up studies.
5,352 downloads genetics
Stephan Schiffels, Wolfgang Haak, Pirita Paajanen, Bastien Llamas, Elizabeth Popescu, Louise Lou, Rachel Clarke, Alice Lyons, Richard Mortimer, Duncan Sayer, Chris Tyler-Smith, Alan Cooper, Richard Durbin
British population history has been shaped by a series of immigrations and internal movements, including the early Anglo-Saxon migrations following the breakdown of the Roman administration after 410CE. It remains an open question how these events affected the genetic composition of the current British population. Here, we present whole-genome sequences generated from ten ancient individuals found in archaeological excavations close to Cambridge in the East of England, ranging from 2,300 until 1,200 years before present (Iron Age to Anglo-Saxon period). We use present-day genetic data to characterize the relationship of these ancient individuals to contemporary British and other European populations. By analyzing the distribution of shared rare variants across ancient and modern individuals, we find that today’s British are more similar to the Iron Age individuals than to most of the Anglo-Saxon individuals, and estimate that the contemporary East English population derives 30% of its ancestry from Anglo-Saxon migrations, with a lower fraction in Wales and Scotland. We gain further insight with a new method, rarecoal, which fits a demographic model to the distribution of shared rare variants across a large number of samples, enabling fine scale analysis of subtle genetic differences and yielding explicit estimates of population sizes and split times. Using rarecoal we find that the ancestors of the Anglo-Saxon samples are closest to modern Danish and Dutch populations, while the Iron Age samples share ancestors with multiple Northern European populations including Britain.
4,953 downloads genetics
In humans and other mammals, female cells carry two X-chromosomes, whereas male cells carry a single X and Y-chromosome. To achieve an equal expression level of X-linked genes in both sexes, a dosage compensation mechanism evolved, which results in transcriptional silencing of one X-chromosome in females. X chromosome inactivation (XCI) is random with respect to the parental origin of the X, occurs early during embryonic development, and is then stably maintained through a near infinite number of cell divisions. As a result of this, every female individual consists of a mosaic of two different cell populations, in which either the maternally or paternally derived X-chromosome is inactivated. As the X-chromosome harbors more than a thousand genes, of which many are implicated in human disease when mutated, this mosaicism has important disease implications. Whereas X-linked disorders are usually more severe in hemizygous males harboring a single X-chromosome, a more variable phenotype is observed in females. This variability is a direct consequence of the XCI-mosaicism, and is affected by the randomness of the XCI process. Here we review the latest insights into the regulation of this important female specific process, and discuss mechanisms that influence mosaicism in females, with a focus on the clinical consequences related to X-linked diseases in females.
4,932 downloads genetics
Polygenic risk scores (PRS) are poised to improve biomedical outcomes via precision medicine. However, the major ethical and scientific challenge surrounding clinical implementation is that they are many-fold more accurate in European ancestry individuals than others. This disparity is an inescapable consequence of Eurocentric genome-wide association study biases. This highlights that--unlike clinical biomarkers and prescription drugs, which may individually work better in some populations but do not ubiquitously perform far better in European populations--clinical uses of PRS today would systematically afford greater improvement to European descent populations. Early diversifying efforts show promise in levelling this vast imbalance, even when non-European sample sizes are considerably smaller than the largest studies to date. To realize the full and equitable potential of PRS, we must prioritize greater diversity in genetic studies and public dissemination of summary statistics to ensure that health disparities are not increased for those already most underserved.
4,923 downloads genetics
As are most non-European populations around the globe, the Han Chinese are relatively understudied in population and medical genetics studies. From low-coverage whole-genome sequencing of 11,670 Han Chinese women we present a catalog of 25,057,223 variants, including 548,401 novel variants that are seen at least 10 times in our dataset. Individuals from our study come from 19 out of 22 provinces across China, allowing us to study population structure, genetic ancestry, and local adaptation in Han Chinese. We identify previously unrecognized population structure along the East-West axis of China and report unique signals of admixture across geographical space, such as European influences among the Northwestern provinces of China. Finally, we identified a number of highly differentiated loci, indicative of local adaptation in the Han Chinese. In particular, we detected extreme differentiation among the Han Chinese at MTHFR, ADH7, and FADS loci, suggesting that these loci may not be specifically selected in Tibetan and Inuit populations as previously suggested. On the other hand, we find that Neandertal ancestry does not vary significantly across the provinces, consistent with admixture prior to the dispersal of modern Han Chinese. Furthermore, contrary to a previous report, Neandertal ancestry does not explain a significant amount of heritability in depression. Our findings provide the largest genetic data set so far made available for Han Chinese and provide insights into the history and population structure of the world's largest ethnic group.
4,915 downloads genetics
The availability of complete human genome sequences from populations across the world has given rise to new population genetic inference methods that explicitly model their ancestral relationship under recombination and mutation. So far, application of these methods to evolutionary history more recent than 20-30 thousand years ago and to population separations has been limited. Here we present a new method that overcomes these shortcomings. The Multiple Sequentially Markovian Coalescent (MSMC) analyses the observed pattern of mutations in multiple individuals, focusing on the first coalescence between any two individuals. Results from applying MSMC to genome sequences from nine populations across the world suggest that the genetic separation of non-African ancestors from African Yoruban ancestors started long before 50,000 years ago, and give information about human population history as recently as 2,000 years ago, including the bottleneck in the peopling of the Americas, and separations within Africa, East Asia and Europe.
4,827 downloads genetics
International Multiple Sclerosis Genetics Consortium, NA Patsopoulos, SE Baranzini, A Santaniello, P Shoostari, C Cotsapas, G Wong, AH Beecham, T James, J Replogle, I Vlachos, C McCabe, T Pers, A Brandes, C White, B Keenan, M Cimpean, P Winn, IP Panteliadis, A Robbins, TFM Andlauer, O Zarzycki, B Dubois, A Goris, H Bach Sondergaard, F Sellebjerg, P Soelberg Sorensen, H Ullum, L Wegner Thoerner, J Saarela, I Cournu Rebeix, V Damotte, B Fontaine, L Guillot Noel, M Lathrop, S Vukusik, A Berthele, V Biberacher, D Buck, C Gasperi, C Graetz, V Grummel, B Hemmer, M Hoshi, B Knier, T Korn, CM Lill, F Luessi, M Mühlau, F Zipp, E Dardiotis, C Agliardi, A Amoroso, N Barizzone, MD Benedetti, L Bernardinelli, P Cavalla, F Clarelli, G Comi, D Cusi, F Esposito, L Ferrè, D Galimberti, C Guaschino, MA Leone, V Martinelli, L Moiola, M Salvetti, M Sorosina, D Vecchio, A Zauli, S Santoro, M Zuccalà, J Mescheriakova, C van Duijn, SD Bos, EG Celius, A Spurkland, M Comabella, X Montalban, L Alfredsson, I Bomfim, D Gomez-Cabrero, J Hillert, M Jagodic, M Lindén, F Piehl, I Jelčić, R Martin, M Sospedra, A Baker, M Ban, C Hawkins, P Hysi, S Kalra, F Karpe, J Khadake, G Lachance, P Molyneux, M Neville, J Thorpe, E Bradshaw, SJ Caillier, P Calabresi, BAC Cree, A Cross, M Davis, PWI de Bakker, S Delgado, M Dembele, K Edwards, K Fitzgerald, IY Frohlich, PA Gourraud, JL Haines, H Hakonarson, D Kimbrough, N Isobe, I Konidari, E Lathi, MH Lee, T Li, D An, A Zimmer, A Lo, L Madireddy, CP Manrique, M Mitrovic, M Olah, E Patrick, MA Pericak-Vance, L Piccio, C Schaefer, H Weiner, K Lage, A Compston, D Hafler, HF Harbo, SL Hauser, G Stewart, S D’Alfonso, G Hadjigeorgiou, B Taylor, LF Barcellos, D Booth, R Hintzen, I Kockum, F Martinelli-Boneschi, JL McCauley, JR Oksenberg, A Oturai, S Sawcer, AJ Ivinson, T Olsson, P.L. De Jager, Murray Barclay, Laurent Peyrin-Biroulet, Mathias Chamaillard, Jean-Frederick Colombe, Mario Cottone, Anthony Croft, Renata D’Incà, Jonas Halfvarson, Katherine Hanigan, Paul Henderson, Jean-Pierre Hugot, Amir Karban, Nicholas A Kennedy, Mohammed Azam Khan, Marc Lémann, Arie Levine, Dunecan Massey, Monica Milla, Grant W. Montgomery, Sok Meng Evelyn Ng, Ioannis Oikonomou, Harald Peeters, Deborah D. Proctor, Jean-Francois Rahier, Rebecca Roberts, Paul Rutgeerts, Frank Seibold, Laura Stronati, Kirstin M. Taylor, Leif Törkvist, Kullak Ublick, Johan Van Limbergen, Andre Van Gossum, Morten H. Vatn, Hu Zhang, Wei Zhang, Australia and New Zealand IBDGC, Belgium Genetic Consortium, Initiative on Crohn and Colitis, NIDDK IBDGC, United Kingdom IBDGC, Wellcome Trust Case Control Consortium
We assembled and analyzed genetic data of 47,351 multiple sclerosis (MS) subjects and 68,284 control subjects and establish a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 independent associations within the extended MHC. We used an ensemble of methods to prioritize up to 551 potentially associated MS susceptibility genes, that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we do find enrichment for MS genes in these brain-resident immune cells. Thus, while MS is most likely initially triggered by perturbation of peripheral immune responses the functional responses of microglia and other brain cells are also altered and may have a role in targeting an autoimmune process to the central nervous system.
4,725 downloads genetics
It is a long standing question as to which genes define the characteristic facial features among different ethnic groups. In this study, we use Uyghurs, an ancient admixed population to query the genetic bases why Europeans and Han Chinese look different. Facial traits were analyzed based on high-dense 3D facial images; numerous biometric spaces were examined for divergent facial features between European and Han Chinese, ranging from inter-landmark distances to dense shape geometrics. Genome-wide association analyses were conducted on a discovery panel of Uyghurs. Six significant loci were identified four of which, rs1868752, rs118078182, rs60159418 at or near UBASH3B, COL23A1, PCDH7 and rs17868256 were replicated in independent cohorts of Uyghurs or Southern Han Chinese. A prospective model was also developed to predict 3D faces based on top GWAS signals, and tested in hypothetic forensic scenarios.
4,609 downloads genetics
Iris E Jansen, Jeanne E Savage, Kyoko Watanabe, Julien Bryois, Dylan M Williams, Stacy Steinberg, Julia Sealock, Ida K. Karlsson, Sara Hägg, Lavinia Athanasiu, Nicola Voyle, Petroula Proitsi, Aree Witoelar, Sven Stringer, Dag Aarsland, Ina S Almdahl, Fred Andersen, Sverre Bergh, Francesco Bettella, Sigurbjorn Bjornsson, Anne Brækhus, Geir Bråthen, Christiaan de Leeuw, Rahul S. Desikan, Srdjan Djurovic, Logan Dumitrescu, Tormod Fladby, Timothy Homan, Palmi V Jonsson, Steven J. Kiddle, K Arvid Rongve, Ingvild Saltvedt, Sigrid B. Sando, Geir Selbæk, Nathan Skenne, Jon Snaedal, Eystein Stordal, Ingun D. Ulstein, Yunpeng Wang, Linda R White, Jens Hjerling-Leffler, Patrick F Sullivan, Wiesje M van der Flier, Richard Dobson, Lea K. Davis, Hreinn Stefansson, Kari Stefansson, Nancy L. Pedersen, Stephan Ripke, Ole A Andreassen, Danielle Posthuma
Late onset Alzheimer's disease (AD) is the most common form of dementia with more than 35 million people affected worldwide, and no curative treatment available. AD is highly heritable and recent genome-wide meta-analyses have identified over 20 genomic loci associated with AD, yet only explaining a small proportion of the genetic variance indicating that undiscovered loci exist. Here, we performed the largest genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 AD cases, 383,378 controls). AD-by-proxy status is based on parental AD diagnosis, and showed strong genetic correlation with AD (rg=0.81). Genetic meta-analysis identified 29 risk loci, of which 9 are novel, and implicating 215 potential causative genes. Independent replication further supports these novel loci in AD. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver and microglia). Furthermore, gene-set analyses indicate the genetic contribution of biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomisation results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying more of the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD to guide new drug development.
4,529 downloads genetics
Jeanne E Savage, Philip R Jansen, Sven Stringer, Kyoko Watanabe, Julien Bryois, Christiaan A de Leeuw, Mats Nagel, Swapnil Awasthi, Peter B. Barr, Jonathan R. I. Coleman, Katrina L. Grasby, Anke R Hammerschlag, Jakob Kaminski, Robert Karlsson, Eva Krapohl, Max Lam, Marianne Nygaard, Chandra A Reynolds, Joey W. Trampush, Hannah Young, Delilah Zabaneh, Sara Hägg, Narelle K. Hansell, Ida K. Karlsson, Sten Linnarsson, Grant W. Montgomery, Ana B Muñoz-Manchado, Erin B. Quinlan, Gunter Schumann, Nathan Skene, Bradley T Webb, Tonya White, Dan E Arking, Deborah K. Attix, Dimitrios Avramopoulos, Robert M. Bilder, Panos Bitsios, Katherine E. Burdick, Tyrone D. Cannon, Ornit Chiba-Falek, Andrea Christoforou, Elizabeth T. Cirulli, Eliza Congdon, Aiden Corvin, Gail Davies, Ian J Deary, Pamela DeRosse, Dwight Dickinson, Srdjan Djurovic, Gary Donohoe, Emily Drabant Conley, Johan G. Eriksson, Thomas Espeseth, Nelson A. Freimer, Stella Giakoumaki, Ina Giegling, Michael Gill, David C Glahn, Ahmad R Hariri, Alex Hatzimanolis, Matthew C. Keller, Emma Knowles, Bettina Konte, Jari Lahti, Stephanie Le Hellard, Todd Lencz, David C Liewald, Edythe London, Astri J. Lundervold, Anil K. Malhotra, Ingrid Melle, Derek Morris, Anna C. Need, William Ollier, Aarno Palotie, Antony Payton, Neil Pendleton, Russell A. Poldrack, Katri Räikkönen, Ivar Reinvang, Panos Roussos, Dan Rujescu, Fred W. Sabb, Matthew A. Scult, Olav B. Smeland, Nikolaos Smyrnis, John M. Starr, Vidar M. Steen, Nikos C. Stefanis, Richard E Straub, Kjetil Sundet, Aristotle N. Voineskos, Daniel R Weinberger, Elisabeth Widen, Jin Yu, Goncalo Abecasis, Ole A Andreassen, Gerome Breen, Lene Christiansen, Birgit Debrabant, Danielle M. Dick, Andreas Heinz, Jens Hjerling-Leffler, M Arfan Ikram, Kenneth S. Kendler, Nicholas G Martin, Sarah E Medland, Nancy L. Pedersen, Robert Plomin, Tinca JC Polderman, Stephan Ripke, Sophie van der Sluis, Patrick F Sullivan, Henning Tiemeier, Scott I Vrieze, Margaret J Wright, Danielle Posthuma
Intelligence is highly heritable and a major determinant of human health and well-being. Recent genome-wide meta-analyses have identified 24 genomic loci linked to intelligence, but much about its genetic underpinnings remains to be discovered. Here, we present the largest genetic association study of intelligence to date (N=279,930), identifying 206 genomic loci (191 novel) and implicating 1,041 genes (963 novel) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and identify 89 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain and specifically in striatal medium spiny neurons and cortical and hippocampal pyramidal neurons. Gene-set analyses implicate pathways related to neurogenesis, neuron differentiation and synaptic structure. We confirm previous strong genetic correlations with several neuropsychiatric disorders, and Mendelian Randomization results suggest protective effects of intelligence for Alzheimer's dementia and ADHD, and bidirectional causation with strong pleiotropy for schizophrenia. These results are a major step forward in understanding the neurobiology of intelligence as well as genetically associated neuropsychiatric traits.
4,516 downloads genetics
A gene drive biases the transmission of a particular allele of a gene such that it is inherited at a greater frequency than by random assortment. Recently, a highly efficient gene drive was developed in insects, which leverages the sequence-targeted DNA cleavage activity of CRISPR/Cas9 and endogenous homology directed repair mechanisms to convert heterozygous genotypes to homozygosity. If implemented in laboratory rodents, this powerful system would enable the rapid assembly of genotypes that involve multiple genes (e.g., to model multigenic human diseases). Such complex genetic models are currently precluded by time, cost, and a requirement for a large number of animals to obtain a few individuals of the desired genotype. However, the efficiency of a CRISPR/Cas9 gene drive system in mammals has not yet been determined. Here, we utilize an active genetic 'CopyCat' element embedded in the mouse Tyrosinase gene to detect genotype conversions after Cas9 activity in the embryo and in the germline. Although Cas9 efficiently induces double strand DNA breaks in the early embryo and is therefore highly mutagenic, these breaks are not resolved by homology directed repair. However, when Cas9 expression is limited to the developing female germline, resulting double strand breaks are resolved by homology directed repair that copies the CopyCat allele from the donor to the receiver chromosome and leads to its super-Mendelian inheritance. These results demonstrate that the CRISPR/Cas9 gene drive mechanism can be implemented to simplify complex genetic crosses in laboratory mice and also contribute valuable data to the ongoing debate about applications to combat invasive rodent populations in island communities.
4,458 downloads genetics
Philip R Jansen, Kyoko Watanabe, Sven Stringer, Nathan Skene, Julien Bryois, Anke R Hammerschlag, Christiaan A de Leeuw, Jeroen Benjamins, Ana B Muñoz-Manchado, Mats Nagel, Jeanne E Savage, Henning Tiemeier, Tonya White, The 23andMe Research Team, Joyce Y Tung, David A. Hinds, Vladimir Vacic, Patrick F Sullivan, Sophie van der Sluis, Tinca JC Polderman, August B. Smit, Jens Hjerling-Leffler, Eus J.W. Van Someren, Danielle Posthuma
Insomnia is the second-most prevalent mental disorder, with no sufficient treatment available. Despite a substantial role of genetic factors, only a handful of genes have been implicated and insight into the associated neurobiological pathways remains limited. Here, we use an unprecedented large genetic association sample (N=1,331,010) to allow detection of a substantial number of genetic variants and gain insight into biological functions, cell types and tissues involved in insomnia. We identify 202 genome-wide significant loci implicating 956 genes through positional, eQTL and chromatin interaction mapping. We show involvement of the axonal part of neurons, of specific cortical and subcortical tissues, and of two specific cell-types in insomnia: striatal medium spiny neurons and hypothalamic neurons. These cell-types have been implicated previously in the regulation of reward processing, sleep and arousal in animal studies, but have never been genetically linked to insomnia in humans. We found weak genetic correlations with other sleep-related traits, but strong genetic correlations with psychiatric and metabolic traits. Mendelian randomization identified causal effects of insomnia on specific psychiatric and metabolic traits. Our findings reveal key brain areas and cells implicated in the neurobiology of insomnia and its related disorders, and provide novel targets for treatment.
4,435 downloads genetics
Marc Haber, Claude Doumet-Serhal, Christiana Scheib, Yali Xue, Petr Danecek, Massimo Mezzavilla, Sonia Youhanna, Rui Martiniano, Javier Prado-Martinez, Michal Szpak, Elizabeth Matisoo-Smith, Holger Schutkowski, Richard Mikulski, Pierre Zalloua, Toomas Kivisild, Chris Tyler-Smith
The Canaanites inhabited the Levant region during the Bronze Age and established a culture which became influential in the Near East and beyond. However, the Canaanites, unlike most other ancient Near Easterners of this period, left few surviving textual records and thus their origin and relationship to ancient and present-day populations remain unclear. In this study, we sequenced five whole-genomes from ~3,700-year-old individuals from the city of Sidon, a major Canaanite city-state on the Eastern Mediterranean coast. We also sequenced the genomes of 99 individuals from present-day Lebanon to catalogue modern Levantine genetic diversity. We find that a Bronze Age Canaanite-related ancestry was widespread in the region, shared among urban populations inhabiting the coast (Sidon) and inland populations (Jordan) who likely lived in farming societies or were pastoral nomads. This Canaanite-related ancestry derived from mixture between local Neolithic populations and eastern migrants genetically related to Chalcolithic Iranians. We estimate, using linkage-disequilibrium decay patterns, that admixture occurred 6,600-3,550 years ago, coinciding with massive population movements in the mid-Holocene triggered by aridification ~4,200 years ago. We show that present-day Lebanese derive most of their ancestry from a Canaanite-related population, which therefore implies substantial genetic continuity in the Levant since at least the Bronze Age. In addition, we find Eurasian ancestry in the Lebanese not present in Bronze Age or earlier Levantines. We estimate this Eurasian ancestry arrived in the Levant around 3,750-2,170 years ago during a period of successive conquests by distant populations such as the Persians and Macedonians.
4,434 downloads genetics
Shane McCarthy, Sayantan Das, Warren Kretzschmar, Olivier Delaneau, Andrew R Wood, Alexander Teumer, Hyun Min Kang, Christian Fuchsberger, Petr Danecek, Kevin Sharp, Yang Luo, Carlo Sidore, Alan Kwong, Nicholas Timpson, Seppo Koskinen, Scott Vrieze, Laura J. Scott, He Zhang, Anubha Mahajan, Jan Veldink, Ulrike Peters, Carlos Pato, Cornelia M. van Duijn, Christopher E Gillies, Ilaria Gandin, Massimo Mezzavilla, Arthur Gilly, Massimiliano Cocca, Michela Traglia, Andrea Angius, Jeffrey Barrett, Dorret I Boomsma, Kari Branham, Gerome Breen, Chad Brummet, Fabio Busonero, Hariy Campbell, Andrew Chan, Sai Chen, Emily Chew, Francis S. Collins, Laura Corbin, George Davey Smith, George Dedoussis, Marcus Dorr, Aliki-Eleni Farmaki, Luigi Ferrucci, Lukas Forer, Ross M Fraser, Stacey Gabriel, Shawn Levy, Leif Groop, Tabitha Harrison, Andrew Hattersley, Oddgeir L Holmen, Kristian Hveem, Matthias Kretzler, James Lee, Matt McGue, Thomas Meitinger, David Melzer, Josine Min, Karen L Mohlke, John Vincent, Matthias Nauck, Deborah Nickerson, Aarno Palotie, Michele Pato, Nicola Pirastu, Melvin Mclnnis, Brent Richards, Cinzia Sala, Veikko Salomaa, David Schlessinger, Sebastian Schoenheer, P. Eline Slagboom, Kerrin Small, Timothy Spector, Dwight Stambolian, Marcus Tuke, Jaakko Tuomilehto, Leonard Van den Berg, Wouter Van Rheenen, Uwe Volker, Cisca Wijmenga, Daniela Toniolo, Eleftheria Zeggini, Paolo Gasparini, Matthew G Sampson, James F Wilson, Timothy Frayling, Paul de Bakker, Morris A. Swertz, Steven McCarroll, Charles Kooperberg, Annelot Dekker, David Altshuler, Cristen Wilier, William Iacono, Samuli Ripatti, Nicole Soranzo, Klaudia Walter, Anand Swaroop, Francesco Cucca, Carl Anderson, Michael Boehnke, Mark I McCarthy, Richard Durbin, Gonçalo Abecasis, Jonathan Marchini
We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1%, a large increase in the number of SNPs tested in association studies and can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.
4,431 downloads genetics
The debate over the ethnogenesis of Ashkenazi Jewry is longstanding, and has been hampered by a lack of Jewish historiographical work between the Biblical and the early Modern eras. Most historians, as well as geneticists, situate them as the descendants of Israelite tribes whose presence in Europe is owed to deportations during the Roman conquest of Palestine, as well as migration from Babylonia, and eventual settlement along the Rhine. By contrast, a few historians and other writers, most famously Arthur Koestler, have looked to migrations following the decline of the little-understood Medieval Jewish kingdom of Khazaria as the main source for Ashkenazi Jewry. A recent study of genetic variation in southeastern European populations (Elhaik 2012) also proposed a Khazarian origin for Ashkenazi Jews, eliciting considerable criticism from other scholars investigating Jewish ancestry who favor a Near Eastern origin of Ashkenazi populations. This paper re-examines the genetic data and analytical approaches used in these studies of Jewish ancestry, and situates them in the context of historical, linguistic, and archaeological evidence from the Caucasus, Europe and the Near East. Based on this reanalysis, it appears not only that the Khazar Hypothesis per se is without serious merit, but also the veracity of the Rhineland Hypothesis may also be questionable.
4,364 downloads genetics
Many important questions in medicine involve questions about causality, For example, do low levels of high-density lipoproteins (HDL) cause heart disease? Does high body mass index (BMI) cause type 2 diabetes? Or are these traits simply correlated in the population for other reasons? A popular approach to answering these problems using human genetics is called "Mendelian randomization". We discuss the prospects and limitations of this approach, and some ways forward.
4,345 downloads genetics
There are ~12 billion nucleotides in every cell of the human body, and there are ~25-100 trillion cells in each human body. Given somatic mosaicism, epigenetic changes and environmental differences, no two human beings are the same, particularly as there are only ~7 billion people on the planet. One of the next great challenges for studying human genetics will be to acknowledge and embrace complexity. Every human is unique, and the study of human disease phenotypes (and phenotypes in general) will be greatly enriched by moving from a deterministic to a more stochastic/probabilistic model. The dichotomous distinction between simple and complex diseases is completely artificial, and we argue instead for a model that considers a spectrum of diseases that are variably manifesting in each person. The rapid adoption of whole genome sequencing (WGS) and the Internet-mediated networking of people promise to yield more insight into this century-old debate. Comprehensive ancestry tracking and detailed family history data, when combined with WGS or at least cascade-carrier screening, might eventually facilitate a degree of genetic prediction for some diseases in the context of their familial and ancestral etiologies. However, it is important to remain humble, as our current state of knowledge is not yet sufficient, and in principle, any number of nucleotides in the genome, if mutated or modified in a certain way and at a certain time and place, might influence some phenotype during embryogenesis or postnatal life.
4,284 downloads genetics
Mark Lipson, Anna Szécsényi-Nagy, Swapan Mallick, Annamária Pósa, Balázs Stégmár, Victoria Keerl, Nadin Rohland, Kristin Stewardson, Matthew Ferry, Megan Michel, Jonas Oppenheimer, Nasreen Broomandkhoshbacht, Eadaoin Harney, Susanne Nordenfelt, Bastien Llamas, Balázs Gusztáv Mende, Kitti Köhler, Krisztián Oross, Mária Bondár, Tibor Marton, Anett Osztás, János Jakucs, Tibor Paluch, Ferenc Horváth, Piroska Csengeri, Judit Koós, Katalin Sebők, Alexandra Anders, Pál Raczky, Judit Regenye, Judit P. Barna, Szilvia Fábián, Gábor Serlegi, Zoltán Toldi, Emese Gyöngyvér Nagy, János Dani, Erika Molnár, György Pálfi, László Márk, Béla Melegh, Zsolt Bánfai, László Domboróczki, Javier Fernández-Eraso, José Antonio Mujika-Alustiza, Carmen Alonso Fernández, Javier Jiménez Echevarría, Ruth Bollongino, Jörg Orschiedt, Kerstin Schierhold, Harald Meller, Alan Cooper, Joachim Burger, Eszter Bánffy, Kurt W. Alt, Carles Lalueza-Fox, Wolfgang Haak, David Reich
Ancient DNA studies have established that European Neolithic populations were descended from Anatolian migrants who received a limited amount of admixture from resident hunter-gatherers. Many open questions remain, however, about the spatial and temporal dynamics of population interactions and admixture during the Neolithic period. Using the highest-resolution genome-wide ancient DNA data set assembled to date --- a total of 177 samples, 127 newly reported here, from the Neolithic and Chalcolithic of Hungary (6000-2900 BCE, n = 98), Germany (5500-3000 BCE, n = 42), and Spain (5500-2200 BCE, n = 37) --- we investigate the population dynamics of Neolithization across Europe. We find that genetic diversity was shaped predominantly by local processes, with varied sources and proportions of hunter-gatherer ancestry among the three regions and through time. Admixture between groups with different ancestry profiles was pervasive and resulted in observable population transformation across almost all cultural transitions. Our results shed new light on the ways that gene flow reshaped European populations throughout the Neolithic period and demonstrate the potential of time-series-based sampling and modeling approaches to elucidate multiple dimensions of historical population interactions.
4,253 downloads genetics
Alexander Gusev, S. Hong Lee, Benjamin M Neale, Gosia Trynka, Bjarni J Vilhjálmsson, Hilary Finucane, Han Xu, Chongzhi Zang, Stephan Ripke, Eli Stahl, Schizophrenia Working Group of the Psychiatric Genomics Consortium, SWE-SCZ Consortium, Anna K Kähler, Christina M Hultman, Shaun M. Purcell, Steven A McCarroll, Mark Daly, Bogdan Pasaniuc, Patrick F Sullivan, Naomi R. Wray, Soumya Raychaudhuri, Alkes L. Price
Common variants implicated by genome-wide association studies (GWAS) of complex diseases are known to be enriched for coding and regulatory variants. We applied methods to partition the heritability explained by genotyped SNPs (h2g) across functional categories (while accounting for shared variance due to linkage disequilibrium) to genotype and imputed data for 11 common diseases. DNaseI Hypersensitivity Sites (DHS) from 218 cell-types, spanning 16% of the genome, explained an average of 79% of h2g (5.1× enrichment; P < 10−20); further enrichment was observed at enhancer and cell-type specific DHS elements. The enrichments were much smaller in analyses that did not use imputed data or were restricted to GWAS- associated SNPs. In contrast, coding variants, spanning 1% of the genome, explained only 8% of h2g (13.8× enrichment; P = 5 × 10−4). We replicated these findings but found no significant contribution from rare coding variants in an independent schizophrenia cohort genotyped on GWAS and exome chips.
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