Genomics

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Hysi PG, Choquet H, Khawaja AP, Wojciechowski R, Tedja MS, Yin J, Simcoe MJ, Patasova K, Mahroo OA, Thai KK, Cumberland PM, Melles RB, Verhoeven VJM, Vitart V, Segre A, Stone RA, Wareham N, Hewitt AW, Mackey DA, Klaver CCW, Macgregor S, for and Myopia CRE, Khaw PT, Foster PJ, and Consortium UKEV, Guggenheim JA, Guggenheim JA, Rahi JS, Jorgenson E, Hammond CJ. Meta-analysis of 542,934 subjects of European ancestry identifies new genes and mechanisms predisposing to refractive error and myopia. Nat Genet 2020;52(4):401-407.Abstract
Refractive errors, in particular myopia, are a leading cause of morbidity and disability worldwide. Genetic investigation can improve understanding of the molecular mechanisms that underlie abnormal eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies (GWAS) that involved 542,934 European participants and identified 336 novel genetic loci associated with refractive error. Collectively, all associated genetic variants explain 18.4% of heritability and improve the accuracy of myopia prediction (area under the curve (AUC) = 0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes that participate in the development of every anatomical component of the eye. In addition, our analyses suggest that genetic factors controlling circadian rhythm and pigmentation are also involved in the development of myopia and refractive error. These results may enable the prediction of refractive error and the development of personalized myopia prevention strategies in the future.
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Iglesias AI, Mishra A, Vitart V, Bykhovskaya Y, Höhn R, Springelkamp H, Cuellar-Partida G, Gharahkhani P, Bailey JCN, Willoughby CE, Li X, Yazar S, Nag A, Khawaja AP, Polašek O, Siscovick D, Mitchell P, Tham YC, Haines JL, Kearns LS, Hayward C, Shi Y, van Leeuwen EM, Taylor KD, Taylor KD, Bonnemaijer P, Rotter JI, Martin NG, Zeller T, Mills RA, Souzeau E, Staffieri SE, Jonas JB, Schmidtmann I, Boutin T, Kang JH, Lucas SEM, Wong TY, Beutel ME, Wilson JF, Wilson JF, Wilson JF, Uitterlinden AG, Vithana EN, Foster PJ, Hysi PG, Hewitt AW, Khor CC, Pasquale LR, Montgomery GW, Klaver CCW, Aung T, Pfeiffer N, Mackey DA, Hammond CJ, Cheng C-Y, Craig JE, Rabinowitz YS, Wiggs JL, Burdon KP, van Duijn CM, Macgregor S. Author Correction: Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases. Nat Commun 2019;10(1):155.Abstract
Emmanuelle Souzeau, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this Article. This has now been corrected in both the PDF and HTML versions of the Article.
Igo RP, Cooke Bailey JN, Romm J, Haines JL, Wiggs JL. Quality Control for the Illumina HumanExome BeadChip. Curr Protoc Hum Genet 2016;90:2.14.1-2.14.16.Abstract

The Illumina HumanExome BeadChip and other exome-based genotyping arrays offer inexpensive genotyping of some 240,000 mostly nonsynonymous coding variants across the human genome. The HumanExome chip, with its highly non-uniform distribution of markers and emphasis on rare coding variants, presents some unique challenges for quality control (QC) and data cleaning. Here, we describe QC procedures for HumanExome data, with examples of challenges specific to exome arrays from our experience cleaning a data set of ∼7,500 samples from the NEIGHBORHOOD Consortium. We focus on standard procedures for QC of genome-wide array data including genotype calling, sex verification, sample identity verification, relationship checking, and population structure that are complicated by the HumanExome panel's enrichment in rare, exonic variation. © 2016 by John Wiley & Sons, Inc.

Imamura M, Takahashi A, Matsunami M, Horikoshi M, Iwata M, Araki S-I, Toyoda M, Susarla G, Ahn J, Park KH, Kong J, Moon S, Sobrin L, and (iDRAGON) IDRGCON, Yamauchi T, Tobe K, Maegawa H, Kadowaki T, Maeda S. Genome-wide association studies identify two novel loci conferring susceptibility to diabetic retinopathy in Japanese patients with type 2 diabetes. Hum Mol Genet 2021;30(8):716-726.Abstract
Several reports have suggested that genetic susceptibility contributes to the development and progression of diabetic retinopathy. We aimed to identify genetic loci that confer susceptibility to diabetic retinopathy in Japanese patients with type 2 diabetes. We analysed 5 790 508 single nucleotide polymorphisms (SNPs) in 8880 Japanese patients with type 2 diabetes, 4839 retinopathy cases and 4041 controls, as well as 2217 independent Japanese patients with type 2 diabetes, 693 retinopathy cases and 1524 controls. The results of these two genome-wide association studies (GWAS) were combined with an inverse variance meta-analysis (Stage-1), followed by de novo genotyping for the candidate SNP loci (P < 1.0 × 10-4) in an independent case-control study (Stage-2, 2260 cases and 723 controls). After combining the association data (Stages 1 and 2) using meta-analysis, the associations of two loci reached a genome-wide significance level: rs12630354 near STT3B on chromosome 3, P = 1.62 × 10-9, odds ratio (OR) = 1.17, 95% confidence interval (CI) 1.11-1.23, and rs140508424 within PALM2 on chromosome 9, P = 4.19 × 10-8, OR = 1.61, 95% CI 1.36-1.91. However, the association of these two loci was not replicated in Korean, European or African American populations. Gene-based analysis using Stage-1 GWAS data identified a gene-level association of EHD3 with susceptibility to diabetic retinopathy (P = 2.17 × 10-6). In conclusion, we identified two novel SNP loci, STT3B and PALM2, and a novel gene, EHD3, that confers susceptibility to diabetic retinopathy; however, further replication studies are required to validate these associations.
Ismail AM, Cui T, Dommaraju K, Singh G, Dehghan S, Seto J, Shrivastava S, Fedorova NB, Gupta N, Stockwell TB, Madupu R, Heim A, Kajon AE, Romanowski EG, Kowalski RP, Malathi J, Therese KL, Madhavan HN, Zhang Q, Ferreyra LJ, Jones MS, Rajaiya J, Dyer DW, Chodosh J, Seto D. Genomic analysis of a large set of currently-and historically-important human adenovirus pathogens. Emerg Microbes Infect 2018;7(1):10.Abstract
Human adenoviruses (HAdVs) are uniquely important "model organisms" as they have been used to elucidate fundamental biological processes, are recognized as complex pathogens, and are used as remedies for human health. As pathogens, HAdVs may effect asymptomatic or mild and severe symptomatic disease upon their infection of respiratory, ocular, gastrointestinal, and genitourinary systems. High-resolution genomic data have enhanced the understanding of HAdV epidemiology, with recombination recognized as an important and major pathway in the molecular evolution and genesis of emergent HAdV pathogens. To support this view and to actualize an algorithm for identifying, characterizing, and typing novel HAdVs, we determined the DNA sequence of 95 isolates from archives containing historically important pathogens and collections housing currently circulating strains to be sequenced. Of the 85 samples that were completely sequenced, 18 novel recombinants within species HAdV-B and D were identified. Two HAdV-D genomes were found to contain novel penton base and fiber genes with significant divergence from known molecular types. In this data set, we found additional isolates of HAdV-D53 and HAdV-D58, two novel genotypes recognized recently using genomics. This supports the thesis that novel HAdV genotypes are not limited to "one-time" appearances of the prototype but are of importance in HAdV epidemiology. These data underscore the significance of lateral genomic transfer in HAdV evolution and reinforce the potential public health impact of novel genotypes of HAdVs emerging in the population.
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Joshi PK, Esko T, Mattsson H, Eklund N, Gandin I, Nutile T, Jackson AU, Schurmann C, Smith AV, Zhang W, Okada Y, Stančáková A, Faul JD, Zhao W, Bartz TM, Concas MP, Franceschini N, Enroth S, Vitart V, Trompet S, Guo X, Chasman DI, O'Connel JR, Corre T, Nongmaithem SS, Chen Y, Mangino M, Ruggiero D, Traglia M, Farmaki A-E, Kacprowski T, Bjonnes A, van der Spek A, Wu Y, Giri AK, Yanek LR, Wang L, Hofer E, Rietveld CA, McLeod O, Cornelis MC, Pattaro C, Verweij N, Baumbach C, Abdellaoui A, Warren HR, Vuckovic D, Mei H, Bouchard C, Perry JRB, Cappellani S, Mirza SS, Benton MC, Broeckel U, Medland SE, Lind PA, Malerba G, Drong A, Yengo L, Bielak LF, Zhi D, van der Most PJ, Shriner D, Mägi R, Hemani G, Karaderi T, Wang Z, Liu T, Demuth I, Zhao JH, Meng W, Lataniotis L, van der Laan SW, Bradfield JP, Wood AR, Bonnefond A, Ahluwalia TS, Hall LM, Salvi E, Yazar S, Carstensen L, de Haan HG, Abney M, Afzal U, Allison MA, Amin N, Asselbergs FW, Bakker SJL, Barr GR, Baumeister SE, Benjamin DJ, Bergmann S, Boerwinkle E, Bottinger EP, Campbell A, Chakravarti A, Chan Y, Chanock SJ, Chen C, Chen IY-D, Collins FS, Connell J, Correa A, Cupples AL, Smith GD, Davies G, Dörr M, Ehret G, Ellis SB, Feenstra B, Feitosa MF, Ford I, Fox CS, Frayling TM, Friedrich N, Geller F, Scotland G, Gillham-Nasenya I, Gottesman O, Graff M, Grodstein F, Gu C, Haley C, Hammond CJ, Harris SE, Harris TB, Hastie ND, Heard-Costa NL, Heikkilä K, Hocking LJ, Homuth G, Hottenga J-J, Huang J, Huffman JE, Hysi PG, Ikram AM, Ingelsson E, Joensuu A, Johansson Å, Jousilahti P, Jukema WJ, Kähönen M, Kamatani Y, Kanoni S, Kerr SM, Khan NM, Koellinger P, Koistinen HA, Kooner MK, Kubo M, Kuusisto J, Lahti J, Launer LJ, Lea RA, Lehne B, Lehtimäki T, Liewald DCM, Lind L, Loh M, Lokki M-L, London SJ, Loomis SJ, Loukola A, Lu Y, Lumley T, Lundqvist A, Männistö S, Marques-Vidal P, Masciullo C, Matchan A, Mathias RA, Matsuda K, Meigs JB, Meisinger C, Meitinger T, Menni C, Mentch FD, Mihailov E, Milani L, Montasser ME, Montgomery GW, Morrison A, Myers RH, Nadukuru R, Navarro P, Nelis M, Nieminen MS, Nolte IM, O'Connor GT, Ogunniyi A, Padmanabhan S, Palmas WR, Pankow JS, Patarcic I, Pavani F, Peyser PA, Pietilainen K, Poulter N, Prokopenko I, Ralhan S, Redmond P, Rich SS, Rissanen H, Robino A, Rose LM, Rose R, Sala C, Salako B, Salomaa V, Sarin A-P, Saxena R, Schmidt H, Scott LJ, Scott WR, Sennblad B, Seshadri S, Sever P, Shrestha S, Smith BH, Smith JA, Soranzo N, Sotoodehnia N, Southam L, Stanton AV, Stathopoulou MG, Strauch K, Strawbridge RJ, Suderman MJ, Tandon N, Tang S-T, Taylor KD, Tayo BO, Töglhofer AM, Tomaszewski M, Tšernikova N, Tuomilehto J, Uitterlinden AG, Vaidya D, van Hylckama Vlieg A, van Setten J, Vasankari T, Vedantam S, Vlachopoulou E, Vozzi D, Vuoksimaa E, Waldenberger M, Ware EB, Wentworth-Shields W, Whitfield JB, Wild S, Willemsen G, Yajnik CS, Yao J, Zaza G, Zhu X, Zhu X, Salem RM, Melbye M, Bisgaard H, Samani NJ, Cusi D, Mackey DA, Cooper RS, Froguel P, Pasterkamp G, Grant SFA, Hakonarson H, Ferrucci L, Scott RA, Morris AD, Palmer CNA, Dedoussis G, Deloukas P, Bertram L, Lindenberger U, Berndt SI, Lindgren CM, Timpson NJ, Tönjes A, Munroe PB, Sørensen TIA, Rotimi CN, Arnett DK, Oldehinkel AJ, Kardia SLR, Balkau B, Gambaro G, Morris AP, Eriksson JG, Wright MJ, Martin NG, Hunt SC, Starr JM, Deary IJ, Griffiths LR, Tiemeier H, Pirastu N, Kaprio J, Wareham NJ, Pérusse L, Wilson JG, Girotto G, Caulfield MJ, Raitakari O, Boomsma DI, Gieger C, van der Harst P, Hicks AA, Kraft P, Sinisalo J, Knekt P, Johannesson M, Magnusson PKE, Hamsten A, Schmidt R, Borecki IB, Vartiainen E, Becker DM, Bharadwaj D, Mohlke KL, Boehnke M, van Duijn CM, Sanghera DK, Teumer A, Zeggini E, Metspalu A, Gasparini P, Ulivi S, Ober C, Toniolo D, Rudan I, Porteous DJ, Ciullo M, Spector TD, Hayward C, Dupuis J, Loos RJF, Wright AF, Chandak GR, Vollenweider P, Shuldiner AR, Ridker PM, Rotter JI, Sattar N, Gyllensten U, North KE, Pirastu M, Psaty BM, Weir DR, Laakso M, Gudnason V, Takahashi A, Chambers JC, Kooner JS, Strachan DP, Campbell H, Hirschhorn JN, Perola M, Polašek O, Wilson JF. Directional dominance on stature and cognition indiverse human populations. Nature 2015;523(7561):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 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 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' 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.

Joshi AD, Andersson C, Buch S, Stender S, Noordam R, Weng L-C, Weeke PE, Auer PL, Boehm B, Chen C, Choi H, Curhan G, Denny JC, De Vivo I, Eicher JD, Ellinghaus D, Folsom AR, Fuchs C, Gala M, Haessler J, Hofman A, Hu F, Hunter DJ, Janssen HLA, Kang JH, Kooperberg C, Kraft P, Kratzer W, Lieb W, Lutsey PL, Darwish Murad S, Nordestgaard BG, Pasquale LR, Reiner AP, Ridker PM, Rimm E, Rose LM, Shaffer CM, Schafmayer C, Tamimi RM, Uitterlinden AG, Völker U, Völzke H, Wakabayashi Y, Wiggs JL, Zhu J, Roden DM, Stricker BH, Tang W, Teumer A, Hampe J, Tybjærg-Hansen A, Chasman DI, Chan AT, Johnson AD. Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies. Gastroenterology 2016;151(2):351-363.e28.Abstract

BACKGROUND & AIMS: A genome-wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale, meta-analysis of GWASs of individuals of European ancestry with available prior genotype data, to identify additional genetic risk factors for gallstone disease. METHODS: We obtained per-allele odds ratio (OR) and standard error estimates using age- and sex-adjusted logistic regression models within each of the 10 discovery studies (8720 cases and 55,152 controls). We performed an inverse variance weighted, fixed-effects meta-analysis of study-specific estimates to identify single-nucleotide polymorphisms that were associated independently with gallstone disease. Associations were replicated in 6489 cases and 62,797 controls. RESULTS: We observed independent associations for 2 single-nucleotide polymorphisms at the ABCG8 locus: rs11887534 (OR, 1.69; 95% confidence interval [CI], 1.54-1.86; P = 2.44 × 10(-60)) and rs4245791 (OR, 1.27; P = 1.90 × 10(-34)). We also identified and/or replicated associations for rs9843304 in TM4SF4 (OR, 1.12; 95% CI, 1.08-1.16; P = 6.09 × 10(-11)), rs2547231 in SULT2A1 (encodes a sulfoconjugation enzyme that acts on hydroxysteroids and cholesterol-derived sterol bile acids) (OR, 1.17; 95% CI, 1.12-1.21; P = 2.24 × 10(-10)), rs1260326 in glucokinase regulatory protein (OR, 1.12; 95% CI, 1.07-1.17; P = 2.55 × 10(-10)), and rs6471717 near CYP7A1 (encodes an enzyme that catalyzes conversion of cholesterol to primary bile acids) (OR, 1.11; 95% CI, 1.08-1.15; P = 8.84 × 10(-9)). Among individuals of African American and Hispanic American ancestry, rs11887534 and rs4245791 were associated positively with gallstone disease risk, whereas the association for the rs1260326 variant was inverse. CONCLUSIONS: In this large-scale GWAS of gallstone disease, we identified 4 loci in genes that have putative functions in cholesterol metabolism and transport, and sulfonylation of bile acids or hydroxysteroids.

Jun G, Ibrahim-Verbaas CA, Vronskaya M, Lambert J-C, Chung J, Naj AC, Kunkle BW, Wang L-S, Bis JC, Bellenguez C, Harold D, Lunetta KL, Destefano AL, Grenier-Boley B, Sims R, Beecham GW, Smith AV, Chouraki V, Hamilton-Nelson KL, Ikram MA, Fievet N, Denning N, Martin ER, Schmidt H, Kamatani Y, Dunstan ML, Valladares O, Laza AR, Zelenika D, Ramirez A, Foroud TM, Choi S-H, Boland A, Becker T, Kukull WA, van der Lee SJ, Pasquier F, Cruchaga C, Beekly D, Fitzpatrick AL, Hanon O, Gill M, Barber R, Gudnason V, Campion D, Love S, Bennett DA, Amin N, Berr C, Tsolaki M, Buxbaum JD, Lopez OL, Deramecourt V, Fox NC, Cantwell LB, Tárraga L, Dufouil C, Hardy J, Crane PK, Eiriksdottir G, Hannequin D, Clarke R, Evans D, Mosley TH, Letenneur L, Brayne C, Maier W, De Jager P, Emilsson V, Dartigues J-F, Hampel H, Kamboh MI, de Bruijn RFAG, Tzourio C, Pastor P, Larson EB, Rotter JI, O'Donovan MC, Montine TJ, Nalls MA, Mead S, Reiman EM, Jonsson PV, Holmes C, St George-Hyslop PH, Boada M, Passmore P, Wendland JR, Schmidt R, Morgan K, Winslow AR, Powell JF, Carasquillo M, Younkin SG, Jakobsdóttir J, Kauwe JSK, Wilhelmsen KC, Rujescu D, Nöthen MM, Hofman A, Jones L, Jones L, Haines JL, Psaty BM, Van Broeckhoven C, Holmans P, Launer LJ, Mayeux R, Lathrop M, Goate AM, Escott-Price V, Seshadri S, Pericak-Vance MA, Amouyel P, Williams J, van Duijn CM, Schellenberg GD, Farrer LA. A novel Alzheimer disease locus located near the gene encoding tau protein. Mol Psychiatry 2016;21(1):108-117.Abstract

APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P⩽1.3 × 10(-8)), frontal cortex (P⩽1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.

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Khateb S, Nassisi M, Bujakowska KM, Méjécase C, Condroyer C, Antonio A, Foussard M, Démontant V, Mohand-Saïd S, Sahel J-A, Zeitz C, Audo I. Longitudinal Clinical Follow-up and Genetic Spectrum of Patients With Rod-Cone Dystrophy Associated With Mutations in PDE6A and PDE6B. JAMA Ophthalmol 2019;Abstract
Importance: A precise phenotypic characterization of retinal dystrophies is needed for disease modeling as a basis for future therapeutic interventions. Objective: To compare genotype, phenotype, and structural changes in patients with rod-cone dystrophy (RCD) associated with mutations in PDE6A or PDE6B. Design, Setting, and Participants: In a retrospective cohort study conducted in Paris, France, from January 2007 to September 2017, 54 patients from a cohort of 1095 index patients with RCD underwent clinical examination, including personal and familial history, best-corrected visual acuity (BCVA), color vision, slitlamp examination, full-field electroretinography, kinetic visual fields (VFs), retinophotography, optical coherence tomography, near-infrared fundus autofluorescence, and short-wavelength fundus autofluorescence imaging. Genotyping was performed using microarray analysis, targeted next-generation sequencing, and Sanger sequencing validation with familial segregation when possible. Data were analyzed from September 1, 2017, to February 1, 2018. Clinical variables were subsequently analyzed in 2018. Main Outcomes and Measures: Phenotype and genotype comparison of patients carrying mutations in PDE6A or PDE6B. Results: Of the 54 patients included in the study, 19 patients of 17 families (11 women [58%]; mean [SD] age at diagnosis, 14.83 [10.63] years) carried pathogenic mutations in PDE6A, and 35 patients of 26 families (17 women [49%]; mean [SD] age at diagnosis, 21.10 [11.56] years) had mutations in PDE6B, accounting for prevalences of 1.6% and 2.4%, respectively. Among 49 identified genetic variants, 14 in PDE6A and 15 in PDE6B were novel. Overall, phenotypic analysis revealed no substantial differences between the 2 groups except for night blindness as a presenting symptom that was noted to be more prevalent in the PDE6A than PDE6B group (80% vs 37%, respectively; P = .005). The mean binocular BCVA and VF decrease over time (measured as mean individual slopes coefficients) was comparable between patients with PDE6A and PDE6B mutations: 0.04 (0.12) vs 0.02 (0.05) for BCVA (P = .89) and 14.33 (7.12) vs 13.27 (6.77) for VF (P = .48). Conclusions and Relevance: Mutations in PDE6A and PDE6B accounted for 1.6% and 2.4%, respectively, in a cohort of French patients with RCD. The functional and structural findings reported may constitute the basis of disease modeling that might be used for better prognostic estimation and candidate selection for photoreceptor therapeutic rescue.
Kim T-K, Hemberg M, Gray JM. Enhancer RNAs: a class of long noncoding RNAs synthesized at enhancers. Cold Spring Harb Perspect Biol 2015;7(1):a018622.Abstract

Recent studies have revealed that active enhancers are transcribed, producing a class of noncoding RNAs called enhancer RNAs (eRNAs). eRNAs are distinct from long noncoding RNAs (lncRNAs), but these two species of noncoding RNAs may share a similar role in the activation of mRNA transcription. Emerging studies, showing that eRNAs function in controlling mRNA transcription, challenge the idea that enhancers are merely sites of transcription factor assembly. Instead, communication between promoters and enhancers can be bidirectional with promoters required to activate enhancer transcription. Reciprocally, eRNAs may then facilitate enhancer-promoter interaction or activate promoter-driven transcription.

Kruszka P, Hu T, Hong S, Signer R, Cogné B, Isidor B, Mazzola SE, Giltay JC, van Gassen KLI, England EM, Pais L, Ockeloen CW, Sanchez-Lara PA, Kinning E, Adams DJ, Treat K, Torres-Martinez W, Bedeschi MF, Iascone M, Blaney S, Bell O, Tan TY, Delrue M-A, Jurgens J, Barry BJ, Engle EC, Savage SK, Fleischer N, Martinez-Agosto JA, Boycott K, Zackai EH, Muenke M. Phenotype delineation of ZNF462 related syndrome. Am J Med Genet A 2019;179(10):2075-2082.Abstract
Zinc finger protein 462 (ZNF462) is a relatively newly discovered vertebrate specific protein with known critical roles in embryonic development in animal models. Two case reports and a case series study have described the phenotype of 10 individuals with ZNF462 loss of function variants. Herein, we present 14 new individuals with loss of function variants to the previous studies to delineate the syndrome of loss of function in ZNF462. Collectively, these 24 individuals present with recurring phenotypes that define a multiple congenital anomaly syndrome. Most have some form of developmental delay (79%) and a minority has autism spectrum disorder (33%). Characteristic facial features include ptosis (83%), down slanting palpebral fissures (58%), exaggerated Cupid's bow/wide philtrum (54%), and arched eyebrows (50%). Metopic ridging or craniosynostosis was found in a third of study participants and feeding problems in half. Other phenotype characteristics include dysgenesis of the corpus callosum in 25% of individuals, hypotonia in half, and structural heart defects in 21%. Using facial analysis technology, a computer algorithm applying deep learning was able to accurately differentiate individuals with ZNF462 loss of function variants from individuals with Noonan syndrome and healthy controls. In summary, we describe a multiple congenital anomaly syndrome associated with haploinsufficiency of ZNF462 that has distinct clinical characteristics and facial features.
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Lamont RE, Tan W-H, Innes MA, Parboosingh JS, Schneidman-Duhovny D, Rajkovic A, Pappas J, Altschwager P, DeWard S, Fulton A, Gray KJ, Krall M, Mehta L, Rodan LH, Saller DN, Steele D, Stein D, Yatsenko SA, Bernier FP, Slavotinek AM. Expansion of phenotype and genotypic data in CRB2-related syndrome. Eur J Hum Genet 2016;24(10):1436-44.Abstract

Sequence variants in CRB2 cause a syndrome with greatly elevated maternal serum alpha-fetoprotein and amniotic fluid alpha-fetoprotein levels, cerebral ventriculomegaly and renal findings similar to Finnish congenital nephrosis. All reported patients have been homozygotes or compound heterozygotes for sequence variants in the Crumbs, Drosophila, Homolog of, 2 (CRB2) genes. Variants affecting CRB2 function have also been identified in four families with steroid resistant nephrotic syndrome, but without any other known systemic findings. We ascertained five, previously unreported individuals with biallelic variants in CRB2 that were predicted to affect function. We compiled the clinical features of reported cases and reviewed available literature for cases with features suggestive of CRB2-related syndrome in order to better understand the phenotypic and genotypic manifestations. Phenotypic analyses showed that ventriculomegaly was a common clinical manifestation (9/11 confirmed cases), in contrast to the original reports, in which patients were ascertained due to renal disease. Two children had minor eye findings and one was diagnosed with a B-cell lymphoma. Further genetic analysis identified one family with two affected siblings who were both heterozygous for a variant in NPHS2 predicted to affect function and separate families with sequence variants in NPHS4 and BBS7 in addition to the CRB2 variants. Our report expands the clinical phenotype of CRB2-related syndrome and establishes ventriculomegaly and hydrocephalus as frequent manifestations. We found additional sequence variants in genes involved in kidney development and ciliopathies in patients with CRB2-related syndrome, suggesting that these variants may modify the phenotype.

Latremoliere A, Cheng L, DeLisle M, Wu C, Chew S, Hutchinson EB, Sheridan A, Alexandre C, Latremoliere F, Sheu S-H, Golidy S, Omura T, Huebner EA, Fan Y, Whitman MC, Nguyen E, Hermawan C, Pierpaoli C, Tischfield MA, Woolf CJ, Engle EC. Neuronal-Specific TUBB3 Is Not Required for Normal Neuronal Function but Is Essential for Timely Axon Regeneration. Cell Rep 2018;24(7):1865-1879.e9.Abstract
We generated a knockout mouse for the neuronal-specific β-tubulin isoform Tubb3 to investigate its role in nervous system formation and maintenance. Tubb3 mice have no detectable neurobehavioral or neuropathological deficits, and upregulation of mRNA and protein of the remaining β-tubulin isotypes results in equivalent total β-tubulin levels in Tubb3 and wild-type mice. Despite similar levels of total β-tubulin, adult dorsal root ganglia lacking TUBB3 have decreased growth cone microtubule dynamics and a decreased neurite outgrowth rate of 22% in vitro and in vivo. The effect of the 22% slower growth rate is exacerbated for sensory recovery, where fibers must reinnervate the full volume of the skin to recover touch function. Overall, these data reveal that, while TUBB3 is not required for formation of the nervous system, it has a specific role in the rate of peripheral axon regeneration that cannot be replaced by other β-tubulins.
Lebreton F, Valentino MD, Duncan LB, Zeng Q, McGuire AM, Earl AM, Gilmore MS. High-Quality Draft Genome Sequence of Vagococcus lutrae Strain LBD1, Isolated from the Largemouth Bass Micropterus salmoides. Genome Announc 2013;1(6)Abstract
Vagococci are usually isolated from marine hosts and occasionally from endodontic infections. Using 16S rRNA gene comparison, the closest relatives are members of the genera Enterococcus and Carnobacterium. A draft sequence of Vagococcus lutrae was generated to clarify the relationship of Vagococcus to these and other related low-G+C Gram-positive bacteria.
Levy JM, Yeh W-H, Pendse N, Davis JR, Hennessey E, Butcher R, Koblan LW, Comander J, Liu Q, Liu DR. Cytosine and adenine base editing of the brain, liver, retina, heart and skeletal muscle of mice via adeno-associated viruses. Nat Biomed Eng 2020;4(1):97-110.Abstract
The success of base editors for the study and treatment of genetic diseases depends on the ability to deliver them in vivo to the relevant cell types. Delivery via adeno-associated viruses (AAVs) is limited by AAV packaging capacity, which precludes the use of full-length base editors. Here, we report the application of dual AAVs for the delivery of split cytosine and adenine base editors that are then reconstituted by trans-splicing inteins. Optimized dual AAVs enable in vivo base editing at therapeutically relevant efficiencies and dosages in the mouse brain (up to 59% of unsorted cortical tissue), liver (38%), retina (38%), heart (20%) and skeletal muscle (9%). We also show that base editing corrects, in mouse brain tissue, a mutation that causes Niemann-Pick disease type C (a neurodegenerative ataxia), slowing down neurodegeneration and increasing lifespan. The optimized delivery vectors should facilitate the efficient introduction of targeted point mutations into multiple tissues of therapeutic interest.
Li Z, Allingham RR, Nakano M, Jia L, Chen Y, Ikeda Y, Mani B, Chen L-J, Kee C, Garway-Heath DF, Sripriya S, Fuse N, Abu-Amero KK, Huang C, Namburi P, Burdon K, Perera SA, Gharahkhani P, Lin Y, Ueno M, Ozaki M, Mizoguchi T, Krishnadas SR, Osman EA, Lee MC, Chan ASY, Tajudin L-SA, Do T, Goncalves A, Reynier P, Zhang H, Bourne R, Goh D, Broadway D, Husain R, Negi AK, Hsu D, Ho C-L, Blanco AA, Leung CKS, Wong TT, Yakub A, Liu Y, Nongpiur ME, Han JC, Hon DN, Shantha B, Zhao B, Sang J, Zhang N, Sato R, Yoshii K, Panda-Jonas S, Ashley Koch AE, Herndon LW, Moroi SE, Challa P, Foo JN, Bei J-X, Zeng Y-X, Simmons CP, Bich Chau TN, Sharmila PF, Chew M, Lim B, Tam POS, Chua E, Ng XY, Yong VHK, Chong YF, Meah WY, Vijayan S, Seongsoo S, Xu W, Teo YY, Cooke Bailey JN, Kang JH, Haines JL, Cheng CY, Saw S-M, Tai E-S, Tai E-S, Tai E-S, Richards JE, Ritch R, Gaasterland DE, Pasquale LR, Liu J, Jonas JB, Milea D, George R, Al-Obeidan SA, Mori K, Macgregor S, Hewitt AW, Girkin CA, Zhang M, Sundaresan P, Vijaya L, Mackey DA, Wong TY, Craig JE, Sun X, Kinoshita S, Wiggs JL, Khor C-C, Yang Z, Pang CP, Wang N, Hauser MA, Tashiro K, Aung T, Vithana EN. A common variant near TGFBR3 is associated with primary open angle glaucoma. Hum Mol Genet 2015;24(13):3880-92.Abstract

Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10(-33)), we observed one SNP showing significant association to POAG (CDC7-TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10(-8)). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis.

Lindström S, Loomis S, Turman C, Huang H, Huang J, Aschard H, Chan AT, Choi H, Cornelis M, Curhan G, De Vivo I, Eliassen HA, Fuchs C, Gaziano M, Hankinson SE, Hu F, Jensen M, Kang JH, Kabrhel C, Liang L, Pasquale LR, Rimm E, Stampfer MJ, Tamimi RM, Tworoger SS, Wiggs JL, Hunter DJ, Kraft P. A comprehensive survey of genetic variation in 20,691 subjects from four large cohorts. PLoS One 2017;12(3):e0173997.Abstract

The Nurses' Health Study (NHS), Nurses' Health Study II (NHSII), Health Professionals Follow Up Study (HPFS) and the Physicians Health Study (PHS) have collected detailed longitudinal data on multiple exposures and traits for approximately 310,000 study participants over the last 35 years. Over 160,000 study participants across the cohorts have donated a DNA sample and to date, 20,691 subjects have been genotyped as part of genome-wide association studies (GWAS) of twelve primary outcomes. However, these studies utilized six different GWAS arrays making it difficult to conduct analyses of secondary phenotypes or share controls across studies. To allow for secondary analyses of these data, we have created three new datasets merged by platform family and performed imputation using a common reference panel, the 1,000 Genomes Phase I release. Here, we describe the methodology behind the data merging and imputation and present imputation quality statistics and association results from two GWAS of secondary phenotypes (body mass index (BMI) and venous thromboembolism (VTE)). We observed the strongest BMI association for the FTO SNP rs55872725 (β = 0.45, p = 3.48x10-22), and using a significance level of p = 0.05, we replicated 19 out of 32 known BMI SNPs. For VTE, we observed the strongest association for the rs2040445 SNP (OR = 2.17, 95% CI: 1.79-2.63, p = 2.70x10-15), located downstream of F5 and also observed significant associations for the known ABO and F11 regions. This pooled resource can be used to maximize power in GWAS of phenotypes collected across the cohorts and for studying gene-environment interactions as well as rare phenotypes and genotypes.

Lonfat N, Cepko C. Epigenomics of Retinal Development in Mice and Humans. Neuron 2017;94(3):420-423.Abstract
In this issue of Neuron, Aldiri et al. (2017) present an analysis of epigenetic changes during retinal development, and use these data to probe reprogramming of retinal iPSC cells, as well as the origin of retinoblastoma cells.
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Machiela MJ, Zhou W, Sampson JN, Dean MC, Jacobs KB, Black A, Brinton LA, Chang I-S, Chen C, Chen C, Chen K, Cook LS, Crous Bou M, De Vivo I, Doherty J, Friedenreich CM, Gaudet MM, Haiman CA, Hankinson SE, Hartge P, Henderson BE, Hong Y-C, Hosgood DH, Hsiung CA, Hu W, Hunter DJ, Jessop L, Kim HN, Kim YH, Kim YT, Klein R, Kraft P, Lan Q, Lin D, Liu J, Le Marchand L, Liang X, Lissowska J, Lu L, Magliocco AM, Matsuo K, Olson SH, Orlow I, Park JY, Pooler L, Prescott J, Rastogi R, Risch HA, Schumacher F, Seow A, Setiawan VW, Shen H, Sheng X, Shin M-H, Shu X-O, Van Den Berg D, Wang J-C, Wentzensen N, Wong MP, Wu C, Wu T, Wu Y-L, Xia L, Yang HP, Yang P-C, Zheng W, Zhou B, Abnet CC, Albanes D, Aldrich MC, Amos C, Amundadottir LT, Berndt SI, Blot WJ, Bock CH, Bracci PM, Burdett L, Buring JE, Butler MA, Carreón T, Chatterjee N, Chung CC, Cook MB, Cullen M, Davis FG, Ding T, Duell EJ, Epstein CG, Fan J-H, Figueroa JD, Fraumeni JF, Freedman ND, Fuchs CS, Gao Y-T, Gapstur SM, Patiño-Garcia A, Garcia-Closas M, Gaziano MJ, Giles GG, Gillanders EM, Giovannucci EL, Goldin L, Goldstein AM, Greene MH, Hallmans G, Harris CC, Henriksson R, Holly EA, Hoover RN, Hu N, Hutchinson A, Jenab M, Johansen C, Khaw K-T, Koh W-P, Kolonel LN, Kooperberg C, Krogh V, Kurtz RC, LaCroix A, Landgren A, Landi MT, Li D, Liao LM, Malats N, McGlynn KA, McNeill LH, McWilliams RR, Melin BS, Mirabello L, Peplonska B, Peters U, Petersen GM, Prokunina-Olsson L, Purdue M, Qiao Y-L, Rabe KG, Rajaraman P, Real FX, Riboli E, Rodríguez-Santiago B, Rothman N, Ruder AM, Savage SA, Schwartz AG, Schwartz KL, Sesso HD, Severi G, Silverman DT, Spitz MR, Stevens VL, Stolzenberg-Solomon R, Stram D, Tang Z-Z, Taylor PR, Teras LR, Tobias GS, Viswanathan K, Wacholder S, Wang Z, Weinstein SJ, Wheeler W, White E, Wiencke JK, Wolpin BM, Wu X, Wunder JS, Yu K, Zanetti KA, Zeleniuch-Jacquotte A, Ziegler RG, deAndrade M, Barnes KC, Beaty TH, Bierut LJ, Desch KC, Doheny KF, Feenstra B, Ginsburg D, Heit JA, Kang JH, Laurie CA, Li JZ, Lowe WL, Marazita ML, Melbye M, Mirel DB, Murray JC, Nelson SC, Pasquale LR, Rice K, Wiggs JL, Wise A, Tucker M, Pérez-Jurado LA, Laurie CC, Caporaso NE, Yeager M, Chanock SJ. Characterization of large structural genetic mosaicism in human autosomes. Am J Hum Genet 2015;96(3):487-97.Abstract

Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.

MacKinnon S, Oystreck DT, Andrews C, Chan W-M, Hunter DG, Engle EC. Diagnostic distinctions and genetic analysis of patients diagnosed with moebius syndrome. Ophthalmology 2014;121(7):1461-8.Abstract
OBJECTIVE: To improve diagnostic assessment in Moebius syndrome by (1) creating more selective diagnostic subgroups and (2) conducting genetic evaluation in a large patient cohort. DESIGN: Prospective, observational study. PARTICIPANTS: Attendees of 3 consecutive Moebius syndrome conferences held in the United States, with a prior diagnosis of Moebius syndrome, were invited to participate. METHODS: Participants underwent standardized ophthalmologic examination for Moebius syndrome minimum diagnostic criteria (MDC) (congenital, nonprogressive facial palsy, and abduction deficit) and genetic testing for HOXA1, HOXB1, and TUBB3 mutations. MAIN OUTCOME MEASURES: The number of patients meeting MDC and the number of patients with confirmed genetic mutation. RESULTS: A total of 112 participants from 107 families enrolled. Nineteen percent of participants (21/112) did not meet accepted MDC for Moebius syndrome because they had abduction deficits without facial palsy or facial palsy with full ocular motility. All 5 families with 2 affected individuals had at least 1 family member in this category, including 2 siblings with comitant strabismus who harbored a HOXB1 mutation. Four unrelated participants, also not meeting MDC, had large-angle exotropia, vertical gaze deficiency, and ptosis consistent with congenital fibrosis of the extraocular muscles type 3 (CFEOM3); 1 patient harbored a novel TUBB3 mutation, and 3 patients harbored previously reported de novo TUBB3 mutations. Three percent of participants (3/112) met MDC but also had restricted vertical gaze. The remaining 88 participants (79%) met MDC and had full vertical gaze. This group had relatively homogeneous findings, and none had a family history of Moebius syndrome. Two previously undescribed phenomena were observed in this category: (1) volitional Bell's phenomenon and (2) intorsion with fixation. CONCLUSIONS: Although the genetic contributors to classic Moebius syndrome remain elusive, accuracy in clinical evaluation will properly subdivide patients to facilitate genetic testing as new candidate genes are identified. Failure to test ocular motility may lead to misdiagnosis of Moebius syndrome, especially in patients who have facial palsy with full ductions. Patients with exotropia, vertical gaze limitation, and ptosis do not have classic Moebius syndrome and may have TUBB3 mutations associated with CFEOM3. To optimize genetic analysis, we propose adding "full vertical motility" to the MDC for Moebius syndrome.

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