@article {10444, title = {Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Jun}, pages = {834-848}, abstract = {

Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0127-7}, author = {Tedja, Milly S and Wojciechowski, Robert and Hysi, Pirro G and Eriksson, Nicholas and Furlotte, Nicholas A and Verhoeven, Virginie J M and Iglesias, Adriana I and Meester-Smoor, Magda A and Tompson, Stuart W and Fan, Qiao and Khawaja, Anthony P and Cheng, Ching-Yu and H{\"o}hn, Ren{\'e} and Yamashiro, Kenji and Wenocur, Adam and Grazal, Clare and Haller, Toomas and Metspalu, Andres and Wedenoja, Juho and Jonas, Jost B and Wang, Ya Xing and Xie, Jing and Mitchell, Paul and Foster, Paul J and Klein, Barbara E K and Klein, Ronald and Paterson, Andrew D and Hosseini, S Mohsen and Shah, Rupal L and Williams, Cathy and Teo, Yik Ying and Tham, Yih Chung and Gupta, Preeti and Zhao, Wanting and Shi, Yuan and Saw, Woei-Yuh and Tai, E-Shyong and Sim, Xue Ling and Huffman, Jennifer E and Polasek, Ozren and Hayward, Caroline and Bencic, Goran and Rudan, Igor and Wilson, James F and Joshi, Peter K and Tsujikawa, Akitaka and Matsuda, Fumihiko and Whisenhunt, Kristina N and Zeller, Tanja and van der Spek, Peter J and Haak, Roxanna and Meijers-Heijboer, Hanne and van Leeuwen, Elisabeth M and Iyengar, Sudha K and Lass, Jonathan H and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Vingerling, Johannes R and Lehtim{\"a}ki, Terho and Raitakari, Olli T and Biino, Ginevra and Concas, Maria Pina and Schwantes-An, Tae-Hwi and Igo, Robert P and Cuellar-Partida, Gabriel and Martin, Nicholas G and Craig, Jamie E and Gharahkhani, Puya and Williams, Katie M and Nag, Abhishek and Rahi, Jugnoo S and Cumberland, Phillippa M and Delcourt, C{\'e}cile and Bellenguez, C{\'e}line and Ried, Janina S and Bergen, Arthur A and Meitinger, Thomas and Gieger, Christian and Wong, Tien Yin and Hewitt, Alex W and Mackey, David A and Simpson, Claire L and Pfeiffer, Norbert and P{\"a}rssinen, Olavi and Baird, Paul N and Vitart, Veronique and Amin, Najaf and van Duijn, Cornelia M and Bailey-Wilson, Joan E and Young, Terri L and Saw, Seang-Mei and Stambolian, Dwight and MacGregor, Stuart and Guggenheim, Jeremy A and Tung, Joyce Y and Hammond, Christopher J and Klaver, Caroline C W} } @article {10430, title = {Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 May}, pages = {652-656}, abstract = {

Hair color is one of the most recognizable visual traits in European populations and is under strong genetic control. Here we report the results of a genome-wide association study meta-analysis of almost 300,000 participants of European descent. We identified 123 autosomal and one X-chromosome loci significantly associated with hair color; all but 13 are novel. Collectively, single-nucleotide polymorphisms associated with hair color within these loci explain 34.6\% of red hair, 24.8\% of blond hair, and 26.1\% of black hair heritability in the study populations. These results confirm the polygenic nature of complex phenotypes and improve our understanding of melanin pigment metabolism in humans.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0100-5}, author = {Hysi, Pirro G and Valdes, Ana M and Liu, Fan and Furlotte, Nicholas A and Evans, David M and Bataille, Veronique and Visconti, Alessia and Hemani, Gibran and McMahon, George and Ring, Susan M and Smith, George Davey and Duffy, David L and Zhu, Gu and Gordon, Scott D and Medland, Sarah E and Lin, Bochao D and Willemsen, Gonneke and Jan Hottenga, Jouke and Vuckovic, Dragana and Girotto, Giorgia and Gandin, Ilaria and Sala, Cinzia and Concas, Maria Pina and Brumat, Marco and Gasparini, Paolo and Toniolo, Daniela and Cocca, Massimiliano and Robino, Antonietta and Yazar, Seyhan and Hewitt, Alex W and Chen, Yan and Zeng, Changqing and Uitterlinden, Andr{\'e} G and Ikram, M Arfan and Hamer, Merel A and van Duijn, Cornelia M and Nijsten, Tamar and Mackey, David A and Falchi, Mario and Boomsma, Dorret I and Martin, Nicholas G and Hinds, David A and Kayser, Manfred and Spector, Timothy D} } @article {10426, title = {A genome-wide association study of corneal astigmatism: The CREAM Consortium.}, journal = {Mol Vis}, volume = {24}, year = {2018}, month = {2018}, pages = {127-142}, abstract = {

Purpose: To identify genes and genetic markers associated with corneal astigmatism.

Methods: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression.

Results: The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha () gene: top SNP: rs7673984, odds ratio=1.12 (95\% CI:1.08-1.16), p=5.55{\texttimes}10. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans-claudin-7 (), acid phosphatase 2, lysosomal (), and TNF alpha-induced protein 8 like 3 ().

Conclusions: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the gene, gene-based analysis identified three novel candidate genes, , , and , that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism.

}, keywords = {Acid Phosphatase, Asian Continental Ancestry Group, Astigmatism, Claudins, Cohort Studies, Cornea, Corneal Diseases, European Continental Ancestry Group, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Intracellular Signaling Peptides and Proteins, Odds Ratio, Polymorphism, Single Nucleotide, Receptor, Platelet-Derived Growth Factor alpha, Software}, issn = {1090-0535}, author = {Shah, Rupal L and Li, Qing and Zhao, Wanting and Tedja, Milly S and Tideman, J Willem L and Khawaja, Anthony P and Fan, Qiao and Yazar, Seyhan and Williams, Katie M and Verhoeven, Virginie J M and Xie, Jing and Wang, Ya Xing and Hess, Moritz and Nickels, Stefan and Lackner, Karl J and P{\"a}rssinen, Olavi and Wedenoja, Juho and Biino, Ginevra and Concas, Maria Pina and Uitterlinden, Andr{\'e} and Rivadeneira, Fernando and Jaddoe, Vincent W V and Hysi, Pirro G and Sim, Xueling and Tan, Nicholas and Tham, Yih-Chung and Sensaki, Sonoko and Hofman, Albert and Vingerling, Johannes R and Jonas, Jost B and Mitchell, Paul and Hammond, Christopher J and H{\"o}hn, Ren{\'e} and Baird, Paul N and Wong, Tien-Yin and Cheng, Chinfsg-Yu and Teo, Yik Ying and Mackey, David A and Williams, Cathy and Saw, Seang-Mei and Klaver, Caroline C W and Guggenheim, Jeremy A and Bailey-Wilson, Joan E} } @article {7696, title = {Directional dominance on stature and cognition in~diverse human populations.}, journal = {Nature}, volume = {523}, year = {2015}, month = {2015 Jul 23}, pages = {459-62}, abstract = {

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs~of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 {\texttimes} 10(-300), 2.1 {\texttimes} 10(-6), 2.5 {\texttimes} 10(-10) and 1.8 {\texttimes} 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months{\textquoteright} less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

}, keywords = {Biological Evolution, Blood Pressure, Body Height, Cholesterol, LDL, Cognition, Cohort Studies, Educational Status, Female, Forced Expiratory Volume, Genome, Human, Homozygote, Humans, Lung Volume Measurements, Male, Phenotype}, issn = {1476-4687}, doi = {10.1038/nature14618}, author = {Joshi, Peter K and Esko, T{\~o}nu and Mattsson, Hannele and Eklund, Niina and Gandin, Ilaria and Nutile, Teresa and Jackson, Anne U and Schurmann, Claudia and Smith, Albert V and Zhang, Weihua and Okada, Yukinori and Stan{\v c}{\'a}kov{\'a}, Alena and Faul, Jessica D and Zhao, Wei and Bartz, Traci M and Concas, Maria Pina and Franceschini, Nora and Enroth, Stefan and Vitart, Veronique and Trompet, Stella and Guo, Xiuqing and Chasman, Daniel I and O{\textquoteright}Connel, Jeffrey R and Corre, Tanguy and Nongmaithem, Suraj S and Chen, Yuning and Mangino, Massimo and Ruggiero, Daniela and Traglia, Michela and Farmaki, Aliki-Eleni and Kacprowski, Tim and Bjonnes, Andrew and van der Spek, Ashley and Wu, Ying and Giri, Anil K and Yanek, Lisa R and Wang, Lihua and Hofer, Edith and Rietveld, Cornelius A and McLeod, Olga and Cornelis, Marilyn C and Pattaro, Cristian and Verweij, Niek and Baumbach, Clemens and Abdellaoui, Abdel and Warren, Helen R and Vuckovic, Dragana and Mei, Hao and Bouchard, Claude and Perry, John R B and Cappellani, Stefania and Mirza, Saira S and Benton, Miles C and Broeckel, Ulrich and Medland, Sarah E and Lind, Penelope A and Malerba, Giovanni and Drong, Alexander and Yengo, Loic and Bielak, Lawrence F and Zhi, Degui and van der Most, Peter J and Shriner, Daniel and M{\"a}gi, Reedik and Hemani, Gibran and Karaderi, Tugce and Wang, Zhaoming and Liu, Tian and Demuth, Ilja and Zhao, Jing Hua and Meng, Weihua and Lataniotis, Lazaros and van der Laan, Sander W and Bradfield, Jonathan P and Wood, Andrew R and Bonnefond, Amelie and Ahluwalia, Tarunveer S and Hall, Leanne M and Salvi, Erika and Yazar, Seyhan and Carstensen, Lisbeth and de Haan, Hugoline G and Abney, Mark and Afzal, Uzma and Allison, Matthew A and Amin, Najaf and Asselbergs, Folkert W and Bakker, Stephan J L and Barr, R Graham and Baumeister, Sebastian E and Benjamin, Daniel J and Bergmann, Sven and Boerwinkle, Eric and Bottinger, Erwin P and Campbell, Archie and Chakravarti, Aravinda and Chan, Yingleong and Chanock, Stephen J and Chen, Constance and Chen, Y-D Ida and Collins, Francis S and Connell, John and Correa, Adolfo and Cupples, L Adrienne and Smith, George Davey and Davies, Gail and D{\"o}rr, Marcus and Ehret, Georg and Ellis, Stephen B and Feenstra, Bjarke and Feitosa, Mary F and Ford, Ian and Fox, Caroline S and Frayling, Timothy M and Friedrich, Nele and Geller, Frank and Scotland, Generation and Gillham-Nasenya, Irina and Gottesman, Omri and Graff, Misa and Grodstein, Francine and Gu, Charles and Haley, Chris and Hammond, Christopher J and Harris, Sarah E and Harris, Tamara B and Hastie, Nicholas D and Heard-Costa, Nancy L and Heikkil{\"a}, Kauko and Hocking, Lynne J and Homuth, Georg and Hottenga, Jouke-Jan and Huang, Jinyan and Huffman, Jennifer E and Hysi, Pirro G and Ikram, M Arfan and Ingelsson, Erik and Joensuu, Anni and Johansson, {\r A}sa and Jousilahti, Pekka and Jukema, J Wouter and K{\"a}h{\"o}nen, Mika and Kamatani, Yoichiro and Kanoni, Stavroula and Kerr, Shona M and Khan, Nazir M and Koellinger, Philipp and Koistinen, Heikki A and Kooner, Manraj K and Kubo, Michiaki and Kuusisto, Johanna and Lahti, Jari and Launer, Lenore J and Lea, Rodney A and Lehne, Benjamin and Lehtim{\"a}ki, Terho and Liewald, David C M and Lind, Lars and Loh, Marie and Lokki, Marja-Liisa and London, Stephanie J and Loomis, Stephanie J and Loukola, Anu and Lu, Yingchang and Lumley, Thomas and Lundqvist, Annamari and M{\"a}nnist{\"o}, Satu and Marques-Vidal, Pedro and Masciullo, Corrado and Matchan, Angela and Mathias, Rasika A and Matsuda, Koichi and Meigs, James B and Meisinger, Christa and Meitinger, Thomas and Menni, Cristina and Mentch, Frank D and Mihailov, Evelin and Milani, Lili and Montasser, May E and Montgomery, Grant W and Morrison, Alanna and Myers, Richard H and Nadukuru, Rajiv and Navarro, Pau and Nelis, Mari and Nieminen, Markku S and Nolte, Ilja M and O{\textquoteright}Connor, George T and Ogunniyi, Adesola and Padmanabhan, Sandosh and Palmas, Walter R and Pankow, James S and Patarcic, Inga and Pavani, Francesca and Peyser, Patricia A and Pietilainen, Kirsi and Poulter, Neil and Prokopenko, Inga and Ralhan, Sarju and Redmond, Paul and Rich, Stephen S and Rissanen, Harri and Robino, Antonietta and Rose, Lynda M and Rose, Richard and Sala, Cinzia and Salako, Babatunde and Salomaa, Veikko and Sarin, Antti-Pekka and Saxena, Richa and Schmidt, Helena and Scott, Laura J and Scott, William R and Sennblad, Bengt and Seshadri, Sudha and Sever, Peter and Shrestha, Smeeta and Smith, Blair H and Smith, Jennifer A and Soranzo, Nicole and Sotoodehnia, Nona and Southam, Lorraine and Stanton, Alice V and Stathopoulou, Maria G and Strauch, Konstantin and Strawbridge, Rona J and Suderman, Matthew J and Tandon, Nikhil and Tang, Sian-Tsun and Taylor, Kent D and Tayo, Bamidele O and T{\"o}glhofer, Anna Maria and Tomaszewski, Maciej and T{\v s}ernikova, Natalia and Tuomilehto, Jaakko and Uitterlinden, Andr{\'e} G and Vaidya, Dhananjay and van Hylckama Vlieg, Astrid and van Setten, Jessica and Vasankari, Tuula and Vedantam, Sailaja and Vlachopoulou, Efthymia and Vozzi, Diego and Vuoksimaa, Eero and Waldenberger, Melanie and Ware, Erin B and Wentworth-Shields, William and Whitfield, John B and Wild, Sarah and Willemsen, Gonneke and Yajnik, Chittaranjan S and Yao, Jie and Zaza, Gianluigi and Zhu, Xiaofeng and Salem, Rany M and Melbye, Mads and Bisgaard, Hans and Samani, Nilesh J and Cusi, Daniele and Mackey, David A and Cooper, Richard S and Froguel, Philippe and Pasterkamp, Gerard and Grant, Struan F A and Hakonarson, Hakon and Ferrucci, Luigi and Scott, Robert A and Morris, Andrew D and Palmer, Colin N A and Dedoussis, George and Deloukas, Panos and Bertram, Lars and Lindenberger, Ulman and Berndt, Sonja I and Lindgren, Cecilia M and Timpson, Nicholas J and T{\"o}njes, Anke and Munroe, Patricia B and S{\o}rensen, Thorkild I A and Rotimi, Charles N and Arnett, Donna K and Oldehinkel, Albertine J and Kardia, Sharon L R and Balkau, Beverley and Gambaro, Giovanni and Morris, Andrew P and Eriksson, Johan G and Wright, Margie J and Martin, Nicholas G and Hunt, Steven C and Starr, John M and Deary, Ian J and Griffiths, Lyn R and Tiemeier, Henning and Pirastu, Nicola and Kaprio, Jaakko and Wareham, Nicholas J and P{\'e}russe, Louis and Wilson, James G and Girotto, Giorgia and Caulfield, Mark J and Raitakari, Olli and Boomsma, Dorret I and Gieger, Christian and van der Harst, Pim and Hicks, Andrew A and Kraft, Peter and Sinisalo, Juha and Knekt, Paul and Johannesson, Magnus and Magnusson, Patrik K E and Hamsten, Anders and Schmidt, Reinhold and Borecki, Ingrid B and Vartiainen, Erkki and Becker, Diane M and Bharadwaj, Dwaipayan and Mohlke, Karen L and Boehnke, Michael and van Duijn, Cornelia M and Sanghera, Dharambir K and Teumer, Alexander and Zeggini, Eleftheria and Metspalu, Andres and Gasparini, Paolo and Ulivi, Sheila and Ober, Carole and Toniolo, Daniela and Rudan, Igor and Porteous, David J and Ciullo, Marina and Spector, Tim D and Hayward, Caroline and Dupuis, Jos{\'e}e and Loos, Ruth J F and Wright, Alan F and Chandak, Giriraj R and Vollenweider, Peter and Shuldiner, Alan R and Ridker, Paul M and Rotter, Jerome I and Sattar, Naveed and Gyllensten, Ulf and North, Kari E and Pirastu, Mario and Psaty, Bruce M and Weir, David R and Laakso, Markku and Gudnason, Vilmundur and Takahashi, Atsushi and Chambers, John C and Kooner, Jaspal S and Strachan, David P and Campbell, Harry and Hirschhorn, Joel N and Perola, Markus and Polasek, Ozren and Wilson, James F} }