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1.  A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants 
Fritsche, Lars G. | Igl, Wilmar | Cooke Bailey, Jessica N. | Grassmann, Felix | Sengupta, Sebanti | Bragg-Gresham, Jennifer L. | Burdon, Kathryn P. | Hebbring, Scott J. | Wen, Cindy | Gorski, Mathias | Kim, Ivana K. | Cho, David | Zack, Donald | Souied, Eric | Scholl, Hendrik P. N. | Bala, Elisa | Lee, Kristine E. | Hunter, David J. | Sardell, Rebecca J. | Mitchell, Paul | Merriam, Joanna E. | Cipriani, Valentina | Hoffman, Joshua D. | Schick, Tina | Lechanteur, Yara T. E. | Guymer, Robyn H. | Johnson, Matthew P. | Jiang, Yingda | Stanton, Chloe M. | Buitendijk, Gabriëlle H. S. | Zhan, Xiaowei | Kwong, Alan M. | Boleda, Alexis | Brooks, Matthew | Gieser, Linn | Ratnapriya, Rinki | Branham, Kari E. | Foerster, Johanna R. | Heckenlively, John R. | Othman, Mohammad I. | Vote, Brendan J. | Liang, Helena Hai | Souzeau, Emmanuelle | McAllister, Ian L. | Isaacs, Timothy | Hall, Janette | Lake, Stewart | Mackey, David A. | Constable, Ian J. | Craig, Jamie E. | Kitchner, Terrie E. | Yang, Zhenglin | Su, Zhiguang | Luo, Hongrong | Chen, Daniel | Ouyang, Hong | Flagg, Ken | Lin, Danni | Mao, Guanping | Ferreyra, Henry | Stark, Klaus | von Strachwitz, Claudia N. | Wolf, Armin | Brandl, Caroline | Rudolph, Guenther | Olden, Matthias | Morrison, Margaux A. | Morgan, Denise J. | Schu, Matthew | Ahn, Jeeyun | Silvestri, Giuliana | Tsironi, Evangelia E. | Park, Kyu Hyung | Farrer, Lindsay A. | Orlin, Anton | Brucker, Alexander | Li, Mingyao | Curcio, Christine | Mohand-Saïd, Saddek | Sahel, José-Alain | Audo, Isabelle | Benchaboune, Mustapha | Cree, Angela J. | Rennie, Christina A. | Goverdhan, Srinivas V. | Grunin, Michelle | Hagbi-Levi, Shira | Campochiaro, Peter | Katsanis, Nicholas | Holz, Frank G. | Blond, Frédéric | Blanché, Hélène | Deleuze, Jean-François | Igo, Robert P. | Truitt, Barbara | Peachey, Neal S. | Meuer, Stacy M. | Myers, Chelsea E. | Moore, Emily L. | Klein, Ronald | Hauser, Michael A. | Postel, Eric A. | Courtenay, Monique D. | Schwartz, Stephen G. | Kovach, Jaclyn L. | Scott, William K. | Liew, Gerald | Tƒan, Ava G. | Gopinath, Bamini | Merriam, John C. | Smith, R. Theodore | Khan, Jane C. | Shahid, Humma | Moore, Anthony T. | McGrath, J. Allie | Laux, Reneé | Brantley, Milam A. | Agarwal, Anita | Ersoy, Lebriz | Caramoy, Albert | Langmann, Thomas | Saksens, Nicole T. M. | de Jong, Eiko K. | Hoyng, Carel B. | Cain, Melinda S. | Richardson, Andrea J. | Martin, Tammy M. | Blangero, John | Weeks, Daniel E. | Dhillon, Bal | van Duijn, Cornelia M. | Doheny, Kimberly F. | Romm, Jane | Klaver, Caroline C. W. | Hayward, Caroline | Gorin, Michael B. | Klein, Michael L. | Baird, Paul N. | den Hollander, Anneke I. | Fauser, Sascha | Yates, John R. W. | Allikmets, Rando | Wang, Jie Jin | Schaumberg, Debra A. | Klein, Barbara E. K. | Hagstrom, Stephanie A. | Chowers, Itay | Lotery, Andrew J. | Léveillard, Thierry | Zhang, Kang | Brilliant, Murray H. | Hewitt, Alex W. | Swaroop, Anand | Chew, Emily Y. | Pericak-Vance, Margaret A. | DeAngelis, Margaret | Stambolian, Dwight | Haines, Jonathan L. | Iyengar, Sudha K. | Weber, Bernhard H. F. | Abecasis, Gonçalo R. | Heid, Iris M.
Nature genetics  2015;48(2):134-143.
Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly with limited therapeutic options. Here, we report on a study of >12 million variants including 163,714 directly genotyped, most rare, protein-altering variant. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5×10–8) distributed across 34 loci. While wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first signal specific to wet AMD, near MMP9 (difference-P = 4.1×10–10). Very rare coding variants (frequency < 0.1%) in CFH, CFI, and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.
PMCID: PMC4745342  PMID: 26691988
2.  Comparing variant calling algorithms for target-exon sequencing in a large sample 
BMC Bioinformatics  2015;16(1):75.
Sequencing studies of exonic regions aim to identify rare variants contributing to complex traits. With high coverage and large sample size, these studies tend to apply simple variant calling algorithms. However, coverage is often heterogeneous; sites with insufficient coverage may benefit from sophisticated calling algorithms used in low-coverage sequencing studies. We evaluate the potential benefits of different calling strategies by performing a comparative analysis of variant calling methods on exonic data from 202 genes sequenced at 24x in 7,842 individuals. We call variants using individual-based, population-based and linkage disequilibrium (LD)-aware methods with stringent quality control. We measure genotype accuracy by the concordance with on-target GWAS genotypes and between 80 pairs of sequencing replicates. We validate selected singleton variants using capillary sequencing.
Using these calling methods, we detected over 27,500 variants at the targeted exons; >57% were singletons. The singletons identified by individual-based analyses were of the highest quality. However, individual-based analyses generated more missing genotypes (4.72%) than population-based (0.47%) and LD-aware (0.17%) analyses. Moreover, individual-based genotypes were the least concordant with array-based genotypes and replicates. Population-based genotypes were less concordant than genotypes from LD-aware analyses with extended haplotypes. We reanalyzed the same dataset with a second set of callers and showed again that the individual-based caller identified more high-quality singletons than the population-based caller. We also replicated this result in a second dataset of 57 genes sequenced at 127.5x in 3,124 individuals.
We recommend population-based analyses for high quality variant calls with few missing genotypes. With extended haplotypes, LD-aware methods generate the most accurate and complete genotypes. In addition, individual-based analyses should complement the above methods to obtain the most singleton variants.
Electronic supplementary material
The online version of this article (doi:10.1186/s12859-015-0489-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4359451  PMID: 25884587
Next-generation sequencing; Targeted sequencing; Variant calling
3.  Rd9 Is a Naturally Occurring Mouse Model of a Common Form of Retinitis Pigmentosa Caused by Mutations in RPGR-ORF15 
PLoS ONE  2012;7(5):e35865.
Animal models of human disease are an invaluable component of studies aimed at understanding disease pathogenesis and therapeutic possibilities. Mutations in the gene encoding retinitis pigmentosa GTPase regulator (RPGR) are the most common cause of X-linked retinitis pigmentosa (XLRP) and are estimated to cause 20% of all retinal dystrophy cases. A majority of RPGR mutations are present in ORF15, the purine-rich terminal exon of the predominant splice-variant expressed in retina. Here we describe the genetic and phenotypic characterization of the retinal degeneration 9 (Rd9) strain of mice, a naturally occurring animal model of XLRP. Rd9 mice were found to carry a 32-base-pair duplication within ORF15 that causes a shift in the reading frame that introduces a premature-stop codon. Rpgr ORF15 transcripts, but not protein, were detected in retinas from Rd9/Y male mice that exhibited retinal pathology, including pigment loss and slowly progressing decrease in outer nuclear layer thickness. The levels of rhodopsin and transducin in rod outer segments were also decreased, and M-cone opsin appeared mislocalized within cone photoreceptors. In addition, electroretinogram (ERG) a- and b-wave amplitudes of both Rd9/Y male and Rd9/Rd9 female mice showed moderate gradual reduction that continued to 24 months of age. The presence of multiple retinal features that correlate with findings in individuals with XLRP identifies Rd9 as a valuable model for use in gaining insight into ORF15-associated disease progression and pathogenesis, as well as accelerating the development and testing of therapeutic strategies for this common form of retinal dystrophy.
PMCID: PMC3341386  PMID: 22563472
4.  A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies 
Nature genetics  2009;41(6):739-745.
Despite rapid advances in disease gene identification, the predictive power of the genotype remains limited, in part due to poorly understood effects of second-site modifiers. Here we demonstrate that a polymorphic coding variant of RPGRIP1L (retinitis pigmentosa GTPase regulator-interacting protein-1 like), a ciliary gene mutated in Meckel-Gruber (MKS) and Joubert (JBTS) syndromes, is associated with the development of retinal degeneration in patients with ciliopathies caused by mutations in other genes. As part of our resequencing efforts of the ciliary proteome, we identified several putative loss of function RPGRIP1L mutations, including one common variant, A229T. Multiple genetic lines of evidence showed this allele to be associated with photoreceptor loss in ciliopathies. Moreover, we show that RPGRIP1L interacts biochemically with RPGR, loss of which causes retinal degeneration, and that the 229T-encoded protein significantly compromises this interaction. Our data represent an example of modification of a discrete phenotype of syndromic disease and highlight the importance of a multifaceted approach for the discovery of modifier alleles of intermediate frequency and effect.
PMCID: PMC2783476  PMID: 19430481

Results 1-4 (4)