%0 Journal Article %J Arch Ophthalmol %D 2009 %T Early age-related macular degeneration, cognitive function, and dementia: the Cardiovascular Health Study. %A Baker, Michelle L %A Wang, Jie Jin %A Rogers, Sophie %A Klein, Ronald %A Kuller, Lewis H %A Larsen, Emily K %A Wong, Tien Yin %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Cognition Disorders %K Dementia %K Female %K Humans %K Intelligence Tests %K Macular Degeneration %K Male %K Neuropsychological Tests %K Odds Ratio %K Prospective Studies %K Risk Factors %K United States %X

OBJECTIVE: To describe the association of cognitive function and dementia with early age-related macular degeneration (AMD) in older individuals.

METHODS: This population-based study included 2,088 persons aged 69 to 97 years who participated in the Cardiovascular Health Study. The AMD was assessed from retinal photographs based on a modified Wisconsin AMD grading system. Cognitive function was assessed using the Digit Symbol Substitution Test (DSST) and the Modified Mini-Mental State Examination. Participants were also evaluated for dementia using detailed neuropsychological testing.

RESULTS: After controlling for age, sex, race, and study center, persons with low DSST scores (lowest quartile of scores, < or =30) were more likely to have early AMD (odds ratio, 1.38; 95% confidence interval, 1.03-1.85) than were persons with higher DSST scores. In analyses further controlling for education, systolic blood pressure, total cholesterol level, diabetes mellitus, smoking status, and apolipoprotein E genotype, this association was stronger (odds ratio, 2.00; 95% confidence interval, 1.29-3.10). There was no association of low Modified Mini-Mental State Examination scores, dementia, or Alzheimer disease with early AMD.

CONCLUSIONS: In this older population, cognitive impairment may share common age-related pathogenesis and risk factors with early AMD.

%B Arch Ophthalmol %V 127 %P 667-73 %8 2009 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/19433718?dopt=Abstract %R 10.1001/archophthalmol.2009.30 %0 Journal Article %J Ann Intern Med %D 2009 %T Meta-analysis: retinal vessel caliber and risk for coronary heart disease. %A McGeechan, Kevin %A Liew, Gerald %A Macaskill, Petra %A Irwig, Les %A Klein, Ronald %A Klein, Barbara E K %A Wang, Jie Jin %A Mitchell, Paul %A Vingerling, Johannes R %A Dejong, Paulus T V M %A Witteman, Jacqueline C M %A Breteler, Monique M B %A Shaw, Jonathan %A Zimmet, Paul %A Wong, Tien Y %K Adult %K Aged %K Arterioles %K Biomarkers %K Coronary Disease %K Female %K Humans %K Male %K Middle Aged %K Proportional Hazards Models %K Retinal Vessels %K Risk Factors %K Sex Factors %K Venules %X

BACKGROUND: Retinal vessel caliber may be a novel marker of coronary heart disease (CHD) risk. However, the sex-specific effect, magnitude of association, and effect independent of traditional CHD disease risk factors remain unclear.

PURPOSE: To determine the association between retinal vessel caliber and risk for CHD.

DATA SOURCES: Relevant studies in any language identified through MEDLINE (1950 to June 2009) and EMBASE (1950 to June 2009) databases.

STUDY SELECTION: Studies were included if they examined a general population, measured retinal vessel caliber from retinal photographs, and documented CHD risk factors and incident CHD events.

DATA EXTRACTION: 6 population-based prospective cohort studies provided data for individual participant meta-analysis.

DATA SYNTHESIS: Proportional hazards models, adjusted for traditional CHD risk factors, were constructed for retinal vessel caliber and incident CHD in women and men. Among 22,159 participants who were free of CHD and followed for 5 to 14 years, 2219 (10.0%) incident CHD events occurred. Retinal vessel caliber changes (wider venules and narrower arterioles) were each associated with an increased risk for CHD in women (pooled multivariable-adjusted hazard ratios, 1.16 [95% CI, 1.06 to 1.26] per 20-microm increase in venular caliber and 1.17 [CI, 1.07 to 1.28] per 20-microm decrease in arteriolar caliber) but not in men (1.02 [CI, 0.94 to 1.10] per 20-microm increase in venular caliber and 1.02 [CI, 0.95 to 1.10] per 20-microm decrease in arteriolar caliber). Women without hypertension or diabetes had higher hazard ratios.

LIMITATION: Error in the measurement of retinal vessel caliber and Framingham variables was not taken into account.

CONCLUSION: Retinal vessel caliber changes were independently associated with an increased risk for CHD events in women.

%B Ann Intern Med %V 151 %P 404-13 %8 2009 Sep 15 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/19755365?dopt=Abstract %0 Journal Article %J Am J Epidemiol %D 2009 %T Prediction of incident stroke events based on retinal vessel caliber: a systematic review and individual-participant meta-analysis. %A McGeechan, Kevin %A Liew, Gerald %A Macaskill, Petra %A Irwig, Les %A Klein, Ronald %A Klein, Barbara E K %A Wang, Jie Jin %A Mitchell, Paul %A Vingerling, Johannes R %A de Jong, Paulus T V M %A Witteman, Jacqueline C M %A Breteler, Monique M B %A Shaw, Jonathan %A Zimmet, Paul %A Wong, Tien Y %K Aged %K Fluorescein Angiography %K Humans %K Middle Aged %K Predictive Value of Tests %K Proportional Hazards Models %K Retinal Artery %K Retinal Vein %K Retinal Vessels %K Risk Factors %K Stroke %X

The caliber of the retinal vessels has been shown to be associated with stroke events. However, the consistency and magnitude of association, and the changes in predicted risk independent of traditional risk factors, are unclear. To determine the association between retinal vessel caliber and the risk of stroke events, the investigators combined individual data from 20,798 people, who were free of stroke at baseline, in 6 cohort studies identified from a search of the Medline (National Library of Medicine, Bethesda, Maryland) and EMBASE (Elsevier B.V., Amsterdam, the Netherlands) databases. During follow-up of 5-12 years, 945 (4.5%) incident stroke events were recorded. Wider retinal venular caliber predicted stroke (pooled hazard ratio = 1.15, 95% confidence interval: 1.05, 1.25 per 20-micron increase in caliber), but the caliber of retinal arterioles was not associated with stroke (pooled hazard ratio = 1.00, 95% confidence interval: 0.92, 1.08). There was weak evidence of heterogeneity in the hazard ratio for retinal venular caliber, which may be attributable to differences in follow-up strategies across studies. Inclusion of retinal venular caliber in prediction models containing traditional stroke risk factors reassigned 10.1% of people at intermediate risk into different, mostly lower, risk categories.

%B Am J Epidemiol %V 170 %P 1323-32 %8 2009 Dec 01 %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/19884126?dopt=Abstract %R 10.1093/aje/kwp306 %0 Journal Article %J PLoS Genet %D 2010 %T Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo. %A Ikram, M Kamran %A Sim, Xueling %A Xueling, Sim %A Jensen, Richard A %A Cotch, Mary Frances %A Hewitt, Alex W %A Ikram, M Arfan %A Wang, Jie Jin %A Klein, Ronald %A Klein, Barbara E K %A Breteler, Monique M B %A Cheung, Ning %A Liew, Gerald %A Mitchell, Paul %A Uitterlinden, André G %A Rivadeneira, Fernando %A Hofman, Albert %A de Jong, Paulus T V M %A van Duijn, Cornelia M %A Kao, Linda %A Cheng, Ching-Yu %A Smith, Albert Vernon %A Glazer, Nicole L %A Lumley, Thomas %A McKnight, Barbara %A Psaty, Bruce M %A Jonasson, Fridbert %A Eiriksdottir, Gudny %A Aspelund, Thor %A Harris, Tamara B %A Launer, Lenore J %A Taylor, Kent D %A Li, Xiaohui %A Iyengar, Sudha K %A Xi, Quansheng %A Sivakumaran, Theru A %A Mackey, David A %A Macgregor, Stuart %A Martin, Nicholas G %A Young, Terri L %A Bis, Josh C %A Wiggins, Kerri L %A Heckbert, Susan R %A Hammond, Christopher J %A Andrew, Toby %A Fahy, Samantha %A Attia, John %A Holliday, Elizabeth G %A Scott, Rodney J %A Islam, F M Amirul %A Rotter, Jerome I %A McAuley, Annie K %A Boerwinkle, Eric %A Tai, E Shyong %A Gudnason, Vilmundur %A Siscovick, David S %A Vingerling, Johannes R %A Wong, Tien Y %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Child %K Child, Preschool %K Chromosomes, Human, Pair 12 %K Chromosomes, Human, Pair 19 %K Chromosomes, Human, Pair 5 %K Chromosomes, Human, Pair 6 %K Cohort Studies %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Meta-Analysis as Topic %K Microcirculation %K Middle Aged %K Polymorphism, Single Nucleotide %K Retinal Vessels %K Young Adult %X

There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n  =  6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10(-8)) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p  =  1.61×10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25×10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p  =  2.15×10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10(-16), adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.

%B PLoS Genet %V 6 %P e1001184 %8 2010 Oct 28 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/21060863?dopt=Abstract %R 10.1371/journal.pgen.1001184 %0 Journal Article %J Invest Ophthalmol Vis Sci %D 2011 %T Candidate gene association study for diabetic retinopathy in persons with type 2 diabetes: the Candidate gene Association Resource (CARe). %A Sobrin, Lucia %A Green, Todd %A Sim, Xueling %A Jensen, Richard A %A Tai, E Shyong %A Tay, Wan Ting %A Wang, Jie Jin %A Mitchell, Paul %A Sandholm, Niina %A Liu, Yiyuan %A Hietala, Kustaa %A Iyengar, Sudha K %A Brooks, Matthew %A Buraczynska, Monika %A Van Zuydam, Natalie %A Smith, Albert V %A Gudnason, Vilmundur %A Doney, Alex S F %A Morris, Andrew D %A Leese, Graham P %A Palmer, Colin N A %A Swaroop, Anand %A Taylor, Herman A %A Wilson, James G %A Penman, Alan %A Chen, Ching J %A Groop, Per-Henrik %A Saw, Seang-Mei %A Aung, Tin %A Klein, Barbara E %A Rotter, Jerome I %A Siscovick, David S %A Cotch, Mary Frances %A Klein, Ronald %A Daly, Mark J %A Wong, Tien Y %K Cardiovascular Diseases %K Diabetes Mellitus, Type 2 %K Diabetic Nephropathies %K Diabetic Retinopathy %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Iduronidase %K Odds Ratio %K P-Selectin %K Polymorphism, Single Nucleotide %K Risk Factors %X

PURPOSE: To investigate whether variants in cardiovascular candidate genes, some of which have been previously associated with type 2 diabetes (T2D), diabetic retinopathy (DR), and diabetic nephropathy (DN), are associated with DR in the Candidate gene Association Resource (CARe).

METHODS: Persons with T2D who were enrolled in the study (n = 2691) had fundus photography and genotyping of single nucleotide polymorphisms (SNPs) in 2000 candidate genes. Two case definitions were investigated: Early Treatment Diabetic Retinopathy Study (ETDRS) grades ≥ 14 and ≥ 30. The χ² analyses for each CARe cohort were combined by Cochran-Mantel-Haenszel (CMH) pooling of odds ratios (ORs) and corrected for multiple hypothesis testing. Logistic regression was performed with adjustment for other DR risk factors. Results from replication in independent cohorts were analyzed with CMH meta-analysis methods.

RESULTS: Among 39 genes previously associated with DR, DN, or T2D, three SNPs in P-selectin (SELP) were associated with DR. The strongest association was to rs6128 (OR = 0.43, P = 0.0001, after Bonferroni correction). These associations remained significant after adjustment for DR risk factors. Among other genes examined, several variants were associated with DR with significant P values, including rs6856425 tagging α-l-iduronidase (IDUA) (P = 2.1 × 10(-5), after Bonferroni correction). However, replication in independent cohorts did not reveal study-wide significant effects. The P values after replication were 0.55 and 0.10 for rs6128 and rs6856425, respectively.

CONCLUSIONS: Genes associated with DN, T2D, and vascular diseases do not appear to be consistently associated with DR. A few genetic variants associated with DR, particularly those in SELP and near IDUA, should be investigated in additional DR cohorts.

%B Invest Ophthalmol Vis Sci %V 52 %P 7593-602 %8 2011 Sep 29 %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/21873659?dopt=Abstract %R 10.1167/iovs.11-7510 %0 Journal Article %J PLoS Genet %D 2012 %T Genome-wide association and functional follow-up reveals new loci for kidney function. %A Pattaro, Cristian %A Köttgen, Anna %A Teumer, Alexander %A Garnaas, Maija %A Böger, Carsten A %A Fuchsberger, Christian %A Olden, Matthias %A Chen, Ming-Huei %A Tin, Adrienne %A Taliun, Daniel %A Li, Man %A Gao, Xiaoyi %A Gorski, Mathias %A Yang, Qiong %A Hundertmark, Claudia %A Foster, Meredith C %A O'Seaghdha, Conall M %A Glazer, Nicole %A Isaacs, Aaron %A Liu, Ching-Ti %A Smith, Albert V %A O'Connell, Jeffrey R %A Struchalin, Maksim %A Tanaka, Toshiko %A Li, Guo %A Johnson, Andrew D %A Gierman, Hinco J %A Feitosa, Mary %A Hwang, Shih-Jen %A Atkinson, Elizabeth J %A Lohman, Kurt %A Cornelis, Marilyn C %A Johansson, Asa %A Tönjes, Anke %A Dehghan, Abbas %A Chouraki, Vincent %A Holliday, Elizabeth G %A Sorice, Rossella %A Kutalik, Zoltán %A Lehtimäki, Terho %A Esko, Tõnu %A Deshmukh, Harshal %A Ulivi, Sheila %A Chu, Audrey Y %A Murgia, Federico %A Trompet, Stella %A Imboden, Medea %A Kollerits, Barbara %A Pistis, Giorgio %A Harris, Tamara B %A Launer, Lenore J %A Aspelund, Thor %A Eiriksdottir, Gudny %A Mitchell, Braxton D %A Boerwinkle, Eric %A Schmidt, Helena %A Cavalieri, Margherita %A Rao, Madhumathi %A Hu, Frank B %A Demirkan, Ayse %A Oostra, Ben A %A de Andrade, Mariza %A Turner, Stephen T %A Ding, Jingzhong %A Andrews, Jeanette S %A Freedman, Barry I %A Koenig, Wolfgang %A Illig, Thomas %A Döring, Angela %A Wichmann, H-Erich %A Kolcic, Ivana %A Zemunik, Tatijana %A Boban, Mladen %A Minelli, Cosetta %A Wheeler, Heather E %A Igl, Wilmar %A Zaboli, Ghazal %A Wild, Sarah H %A Wright, Alan F %A Campbell, Harry %A Ellinghaus, David %A Nöthlings, Ute %A Jacobs, Gunnar %A Biffar, Reiner %A Endlich, Karlhans %A Ernst, Florian %A Homuth, Georg %A Kroemer, Heyo K %A Nauck, Matthias %A Stracke, Sylvia %A Völker, Uwe %A Völzke, Henry %A Kovacs, Peter %A Stumvoll, Michael %A Mägi, Reedik %A Hofman, Albert %A Uitterlinden, André G %A Rivadeneira, Fernando %A Aulchenko, Yurii S %A Polasek, Ozren %A Hastie, Nick %A Vitart, Veronique %A Helmer, Catherine %A Wang, Jie Jin %A Ruggiero, Daniela %A Bergmann, Sven %A Kähönen, Mika %A Viikari, Jorma %A Nikopensius, Tiit %A Province, Michael %A Ketkar, Shamika %A Colhoun, Helen %A Doney, Alex %A Robino, Antonietta %A Giulianini, Franco %A Krämer, Bernhard K %A Portas, Laura %A Ford, Ian %A Buckley, Brendan M %A Adam, Martin %A Thun, Gian-Andri %A Paulweber, Bernhard %A Haun, Margot %A Sala, Cinzia %A Metzger, Marie %A Mitchell, Paul %A Ciullo, Marina %A Kim, Stuart K %A Vollenweider, Peter %A Raitakari, Olli %A Metspalu, Andres %A Palmer, Colin %A Gasparini, Paolo %A Pirastu, Mario %A Jukema, J Wouter %A Probst-Hensch, Nicole M %A Kronenberg, Florian %A Toniolo, Daniela %A Gudnason, Vilmundur %A Shuldiner, Alan R %A Coresh, Josef %A Schmidt, Reinhold %A Ferrucci, Luigi %A Siscovick, David S %A van Duijn, Cornelia M %A Borecki, Ingrid %A Kardia, Sharon L R %A Liu, Yongmei %A Curhan, Gary C %A Rudan, Igor %A Gyllensten, Ulf %A Wilson, James F %A Franke, Andre %A Pramstaller, Peter P %A Rettig, Rainer %A Prokopenko, Inga %A Witteman, Jacqueline C M %A Hayward, Caroline %A Ridker, Paul %A Parsa, Afshin %A Bochud, Murielle %A Heid, Iris M %A Goessling, Wolfram %A Chasman, Daniel I %A Kao, W H Linda %A Fox, Caroline S %K African Americans %K Aged %K Animals %K Caspase 9 %K Cyclin-Dependent Kinases %K DEAD-box RNA Helicases %K DNA Helicases %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Gene Knockdown Techniques %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Kidney %K Kidney Failure, Chronic %K Male %K Middle Aged %K Phosphoric Diester Hydrolases %K Zebrafish %X

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

%B PLoS Genet %V 8 %P e1002584 %8 2012 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/22479191?dopt=Abstract %R 10.1371/journal.pgen.1002584 %0 Journal Article %J J Am Soc Nephrol %D 2013 %T Common variants in Mendelian kidney disease genes and their association with renal function. %A Parsa, Afshin %A Fuchsberger, Christian %A Köttgen, Anna %A O'Seaghdha, Conall M %A Pattaro, Cristian %A de Andrade, Mariza %A Chasman, Daniel I %A Teumer, Alexander %A Endlich, Karlhans %A Olden, Matthias %A Chen, Ming-Huei %A Tin, Adrienne %A Kim, Young J %A Taliun, Daniel %A Li, Man %A Feitosa, Mary %A Gorski, Mathias %A Yang, Qiong %A Hundertmark, Claudia %A Foster, Meredith C %A Glazer, Nicole %A Isaacs, Aaron %A Rao, Madhumathi %A Smith, Albert V %A O'Connell, Jeffrey R %A Struchalin, Maksim %A Tanaka, Toshiko %A Li, Guo %A Hwang, Shih-Jen %A Atkinson, Elizabeth J %A Lohman, Kurt %A Cornelis, Marilyn C %A Johansson, Asa %A Tönjes, Anke %A Dehghan, Abbas %A Couraki, Vincent %A Holliday, Elizabeth G %A Sorice, Rossella %A Kutalik, Zoltán %A Lehtimäki, Terho %A Esko, Tõnu %A Deshmukh, Harshal %A Ulivi, Sheila %A Chu, Audrey Y %A Murgia, Federico %A Trompet, Stella %A Imboden, Medea %A Kollerits, Barbara %A Pistis, Giorgio %A Harris, Tamara B %A Launer, Lenore J %A Aspelund, Thor %A Eiriksdottir, Gudny %A Mitchell, Braxton D %A Boerwinkle, Eric %A Schmidt, Helena %A Hofer, Edith %A Hu, Frank %A Demirkan, Ayse %A Oostra, Ben A %A Turner, Stephen T %A Ding, Jingzhong %A Andrews, Jeanette S %A Freedman, Barry I %A Giulianini, Franco %A Koenig, Wolfgang %A Illig, Thomas %A Döring, Angela %A Wichmann, H-Erich %A Zgaga, Lina %A Zemunik, Tatijana %A Boban, Mladen %A Minelli, Cosetta %A Wheeler, Heather E %A Igl, Wilmar %A Zaboli, Ghazal %A Wild, Sarah H %A Wright, Alan F %A Campbell, Harry %A Ellinghaus, David %A Nöthlings, Ute %A Jacobs, Gunnar %A Biffar, Reiner %A Ernst, Florian %A Homuth, Georg %A Kroemer, Heyo K %A Nauck, Matthias %A Stracke, Sylvia %A Völker, Uwe %A Völzke, Henry %A Kovacs, Peter %A Stumvoll, Michael %A Mägi, Reedik %A Hofman, Albert %A Uitterlinden, André G %A Rivadeneira, Fernando %A Aulchenko, Yurii S %A Polasek, Ozren %A Hastie, Nick %A Vitart, Veronique %A Helmer, Catherine %A Wang, Jie Jin %A Stengel, Bénédicte %A Ruggiero, Daniela %A Bergmann, Sven %A Kähönen, Mika %A Viikari, Jorma %A Nikopensius, Tiit %A Province, Michael %A Colhoun, Helen %A Doney, Alex %A Robino, Antonietta %A Krämer, Bernhard K %A Portas, Laura %A Ford, Ian %A Buckley, Brendan M %A Adam, Martin %A Thun, Gian-Andri %A Paulweber, Bernhard %A Haun, Margot %A Sala, Cinzia %A Mitchell, Paul %A Ciullo, Marina %A Vollenweider, Peter %A Raitakari, Olli %A Metspalu, Andres %A Palmer, Colin %A Gasparini, Paolo %A Pirastu, Mario %A Jukema, J Wouter %A Probst-Hensch, Nicole M %A Kronenberg, Florian %A Toniolo, Daniela %A Gudnason, Vilmundur %A Shuldiner, Alan R %A Coresh, Josef %A Schmidt, Reinhold %A Ferrucci, Luigi %A van Duijn, Cornelia M %A Borecki, Ingrid %A Kardia, Sharon L R %A Liu, Yongmei %A Curhan, Gary C %A Rudan, Igor %A Gyllensten, Ulf %A Wilson, James F %A Franke, Andre %A Pramstaller, Peter P %A Rettig, Rainer %A Prokopenko, Inga %A Witteman, Jacqueline %A Hayward, Caroline %A Ridker, Paul M %A Bochud, Murielle %A Heid, Iris M %A Siscovick, David S %A Fox, Caroline S %A Kao, W Linda %A Böger, Carsten A %K Databases, Genetic %K European Continental Ancestry Group %K Gene Frequency %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Kidney %K Mendelian Randomization Analysis %K Phenotype %K Polymorphism, Single Nucleotide %K Renal Insufficiency, Chronic %X

Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.

%B J Am Soc Nephrol %V 24 %P 2105-17 %8 2013 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/24029420?dopt=Abstract %R 10.1681/ASN.2012100983 %0 Journal Article %J PLoS One %D 2013 %T Genetic loci for retinal arteriolar microcirculation. %A Sim, Xueling %A Jensen, Richard A %A Ikram, M Kamran %A Cotch, Mary Frances %A Li, Xiaohui %A Macgregor, Stuart %A Xie, Jing %A Smith, Albert Vernon %A Boerwinkle, Eric %A Mitchell, Paul %A Klein, Ronald %A Klein, Barbara E K %A Glazer, Nicole L %A Lumley, Thomas %A McKnight, Barbara %A Psaty, Bruce M %A de Jong, Paulus T V M %A Hofman, Albert %A Rivadeneira, Fernando %A Uitterlinden, André G %A van Duijn, Cornelia M %A Aspelund, Thor %A Eiriksdottir, Gudny %A Harris, Tamara B %A Jonasson, Fridbert %A Launer, Lenore J %A Attia, John %A Baird, Paul N %A Harrap, Stephen %A Holliday, Elizabeth G %A Inouye, Michael %A Rochtchina, Elena %A Scott, Rodney J %A Viswanathan, Ananth %A Li, Guo %A Smith, Nicholas L %A Wiggins, Kerri L %A Kuo, Jane Z %A Taylor, Kent D %A Hewitt, Alex W %A Martin, Nicholas G %A Montgomery, Grant W %A Sun, Cong %A Young, Terri L %A Mackey, David A %A van Zuydam, Natalie R %A Doney, Alex S F %A Palmer, Colin N A %A Morris, Andrew D %A Rotter, Jerome I %A Tai, E Shyong %A Gudnason, Vilmundur %A Vingerling, Johannes R %A Siscovick, David S %A Wang, Jie Jin %A Wong, Tien Y %K Aged %K Aged, 80 and over %K Arterioles %K Chromosomes, Human, Pair 5 %K European Continental Ancestry Group %K Female %K Genetic Loci %K Genome-Wide Association Study %K Genotype %K Humans %K Male %K MEF2 Transcription Factors %K Microcirculation %K Middle Aged %K Models, Genetic %K Retinal Vessels %X

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10(-8). This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10(-12) in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.

%B PLoS One %V 8 %P e65804 %8 2013 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23776548?dopt=Abstract %R 10.1371/journal.pone.0065804 %0 Journal Article %J PLoS One %D 2013 %T Genome-wide association study of retinopathy in individuals without diabetes. %A Jensen, Richard A %A Sim, Xueling %A Li, Xiaohui %A Cotch, Mary Frances %A Ikram, M Kamran %A Holliday, Elizabeth G %A Eiriksdottir, Gudny %A Harris, Tamara B %A Jonasson, Fridbert %A Klein, Barbara E K %A Launer, Lenore J %A Smith, Albert Vernon %A Boerwinkle, Eric %A Cheung, Ning %A Hewitt, Alex W %A Liew, Gerald %A Mitchell, Paul %A Wang, Jie Jin %A Attia, John %A Scott, Rodney %A Glazer, Nicole L %A Lumley, Thomas %A McKnight, Barbara %A Psaty, Bruce M %A Taylor, Kent %A Hofman, Albert %A de Jong, Paulus T V M %A Rivadeneira, Fernando %A Uitterlinden, André G %A Tay, Wan-Ting %A Teo, Yik Ying %A Seielstad, Mark %A Liu, Jianjun %A Cheng, Ching-Yu %A Saw, Seang-Mei %A Aung, Tin %A Ganesh, Santhi K %A O'Donnell, Christopher J %A Nalls, Mike A %A Wiggins, Kerri L %A Kuo, Jane Z %A van Duijn, Cornelia M %A Gudnason, Vilmundur %A Klein, Ronald %A Siscovick, David S %A Rotter, Jerome I %A Tai, E Shong %A Vingerling, Johannes %A Wong, Tien Y %K Aged %K Aged, 80 and over %K Female %K Genome-Wide Association Study %K Genotype %K Histone Deacetylases %K Humans %K Hypertension %K Male %K Polymorphism, Single Nucleotide %K Repressor Proteins %K Retinal Diseases %X

BACKGROUND: Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes.

METHODS: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy.

RESULTS: No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, -1.3±0.23 (beta ± standard error), p = 6.6×10(-9). Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%), the quality of the imputation was moderate (r(2) ∼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension.

CONCLUSIONS: This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.

%B PLoS One %V 8 %P e54232 %8 2013 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23393555?dopt=Abstract %R 10.1371/journal.pone.0054232 %0 Journal Article %J PLoS One %D 2013 %T Insights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis. %A Holliday, Elizabeth G %A Smith, Albert V %A Cornes, Belinda K %A Buitendijk, Gabriëlle H S %A Jensen, Richard A %A Sim, Xueling %A Aspelund, Thor %A Aung, Tin %A Baird, Paul N %A Boerwinkle, Eric %A Cheng, Ching Yu %A van Duijn, Cornelia M %A Eiriksdottir, Gudny %A Gudnason, Vilmundur %A Harris, Tamara %A Hewitt, Alex W %A Inouye, Michael %A Jonasson, Fridbert %A Klein, Barbara E K %A Launer, Lenore %A Li, Xiaohui %A Liew, Gerald %A Lumley, Thomas %A McElduff, Patrick %A McKnight, Barbara %A Mitchell, Paul %A Psaty, Bruce M %A Rochtchina, Elena %A Rotter, Jerome I %A Scott, Rodney J %A Tay, Wanting %A Taylor, Kent %A Teo, Yik Ying %A Uitterlinden, André G %A Viswanathan, Ananth %A Xie, Sophia %A Vingerling, Johannes R %A Klaver, Caroline C W %A Tai, E Shyong %A Siscovick, David %A Klein, Ronald %A Cotch, Mary Frances %A Wong, Tien Y %A Attia, John %A Wang, Jie Jin %K Apolipoproteins E %K Complement Factor H %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genotype %K Humans %K Kruppel-Like Transcription Factors %K Macular Degeneration %K Nerve Tissue Proteins %K Polymorphism, Single Nucleotide %K Proteins %K Risk Factors %K Zinc Finger Protein Gli3 %X

Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5×10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3×10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1×10(-6)) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9×10(-6)) and upstream of GLI2 (rs6721654; P = 6.5×10(-6)), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5×10(-6)), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.

%B PLoS One %V 8 %P e53830 %8 2013 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23326517?dopt=Abstract %R 10.1371/journal.pone.0053830 %0 Journal Article %J Hum Mol Genet %D 2016 %T A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration. %A de Vries, Paul S %A Chasman, Daniel I %A Sabater-Lleal, Maria %A Chen, Ming-Huei %A Huffman, Jennifer E %A Steri, Maristella %A Tang, Weihong %A Teumer, Alexander %A Marioni, Riccardo E %A Grossmann, Vera %A Hottenga, Jouke J %A Trompet, Stella %A Müller-Nurasyid, Martina %A Zhao, Jing Hua %A Brody, Jennifer A %A Kleber, Marcus E %A Guo, Xiuqing %A Wang, Jie Jin %A Auer, Paul L %A Attia, John R %A Yanek, Lisa R %A Ahluwalia, Tarunveer S %A Lahti, Jari %A Venturini, Cristina %A Tanaka, Toshiko %A Bielak, Lawrence F %A Joshi, Peter K %A Rocanin-Arjo, Ares %A Kolcic, Ivana %A Navarro, Pau %A Rose, Lynda M %A Oldmeadow, Christopher %A Riess, Helene %A Mazur, Johanna %A Basu, Saonli %A Goel, Anuj %A Yang, Qiong %A Ghanbari, Mohsen %A Willemsen, Gonneke %A Rumley, Ann %A Fiorillo, Edoardo %A de Craen, Anton J M %A Grotevendt, Anne %A Scott, Robert %A Taylor, Kent D %A Delgado, Graciela E %A Yao, Jie %A Kifley, Annette %A Kooperberg, Charles %A Qayyum, Rehan %A Lopez, Lorna M %A Berentzen, Tina L %A Räikkönen, Katri %A Mangino, Massimo %A Bandinelli, Stefania %A Peyser, Patricia A %A Wild, Sarah %A Trégouët, David-Alexandre %A Wright, Alan F %A Marten, Jonathan %A Zemunik, Tatijana %A Morrison, Alanna C %A Sennblad, Bengt %A Tofler, Geoffrey %A de Maat, Moniek P M %A de Geus, Eco J C %A Lowe, Gordon D %A Zoledziewska, Magdalena %A Sattar, Naveed %A Binder, Harald %A Völker, Uwe %A Waldenberger, Melanie %A Khaw, Kay-Tee %A McKnight, Barbara %A Huang, Jie %A Jenny, Nancy S %A Holliday, Elizabeth G %A Qi, Lihong %A Mcevoy, Mark G %A Becker, Diane M %A Starr, John M %A Sarin, Antti-Pekka %A Hysi, Pirro G %A Hernandez, Dena G %A Jhun, Min A %A Campbell, Harry %A Hamsten, Anders %A Rivadeneira, Fernando %A McArdle, Wendy L %A Slagboom, P Eline %A Zeller, Tanja %A Koenig, Wolfgang %A Psaty, Bruce M %A Haritunians, Talin %A Liu, Jingmin %A Palotie, Aarno %A Uitterlinden, André G %A Stott, David J %A Hofman, Albert %A Franco, Oscar H %A Polasek, Ozren %A Rudan, Igor %A Morange, Pierre-Emmanuel %A Wilson, James F %A Kardia, Sharon L R %A Ferrucci, Luigi %A Spector, Tim D %A Eriksson, Johan G %A Hansen, Torben %A Deary, Ian J %A Becker, Lewis C %A Scott, Rodney J %A Mitchell, Paul %A März, Winfried %A Wareham, Nick J %A Peters, Annette %A Greinacher, Andreas %A Wild, Philipp S %A Jukema, J Wouter %A Boomsma, Dorret I %A Hayward, Caroline %A Cucca, Francesco %A Tracy, Russell %A Watkins, Hugh %A Reiner, Alex P %A Folsom, Aaron R %A Ridker, Paul M %A O'Donnell, Christopher J %A Smith, Nicholas L %A Strachan, David P %A Dehghan, Abbas %X

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

%B Hum Mol Genet %V 25 %P 358-70 %8 2016 Jan 15 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26561523?dopt=Abstract %R 10.1093/hmg/ddv454 %0 Journal Article %J Circ Cardiovasc Genet %D 2016 %T Novel Genetic Loci Associated With Retinal Microvascular Diameter. %A Jensen, Richard A %A Sim, Xueling %A Smith, Albert Vernon %A Li, Xiaohui %A Jakobsdottir, Johanna %A Cheng, Ching-Yu %A Brody, Jennifer A %A Cotch, Mary Frances %A McKnight, Barbara %A Klein, Ronald %A Wang, Jie Jin %A Kifley, Annette %A Harris, Tamara B %A Launer, Lenore J %A Taylor, Kent D %A Klein, Barbara E K %A Raffel, Leslie J %A Li, Xiang %A Ikram, M Arfan %A Klaver, Caroline C %A van der Lee, Sven J %A Mutlu, Unal %A Hofman, Albert %A Uitterlinden, André G %A Liu, Chunyu %A Kraja, Aldi T %A Mitchell, Paul %A Gudnason, Vilmundur %A Rotter, Jerome I %A Boerwinkle, Eric %A van Duijn, Cornelia M %A Psaty, Bruce M %A Wong, Tien Y %X

BACKGROUND: There is increasing evidence that retinal microvascular diameters are associated with cardiovascular and cerebrovascular conditions. The shared genetic effects of these associations are currently unknown. The aim of this study was to increase our understanding of the genetic factors that mediate retinal vessel size.

METHODS AND RESULTS: This study extends previous genome-wide association study results using 24 000+ multiethnic participants from 7 discovery cohorts and 5000+ subjects of European ancestry from 2 replication cohorts. Using the Illumina HumanExome BeadChip, we investigate the association of single-nucleotide polymorphisms and variants collectively across genes with summary measures of retinal vessel diameters, referred to as the central retinal venule equivalent and the central retinal arteriole equivalent. We report 4 new loci associated with central retinal venule equivalent, one of which is also associated with central retinal arteriole equivalent. The 4 single-nucleotide polymorphisms are rs7926971 in TEAD1 (P=3.1×10(-) (11); minor allele frequency=0.43), rs201259422 in TSPAN10 (P=4.4×10(-9); minor allele frequency=0.27), rs5442 in GNB3 (P=7.0×10(-10); minor allele frequency=0.05), and rs1800407 in OCA2 (P=3.4×10(-8); minor allele frequency=0.05). The latter single-nucleotide polymorphism, rs1800407, was also associated with central retinal arteriole equivalent (P=6.5×10(-12)). Results from the gene-based burden tests were null. In phenotype look-ups, single-nucleotide polymorphism rs201255422 was associated with both systolic (P=0.001) and diastolic blood pressures (P=8.3×10(-04)).

CONCLUSIONS: Our study expands the understanding of genetic factors influencing the size of the retinal microvasculature. These findings may also provide insight into the relationship between retinal and systemic microvascular disease.

%B Circ Cardiovasc Genet %V 9 %P 45-54 %8 2016 Feb %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26567291?dopt=Abstract %R 10.1161/CIRCGENETICS.115.001142 %0 Journal Article %J J Am Soc Nephrol %D 2016 %T SOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function. %A Li, Man %A Li, Yong %A Weeks, Olivia %A Mijatovic, Vladan %A Teumer, Alexander %A Huffman, Jennifer E %A Tromp, Gerard %A Fuchsberger, Christian %A Gorski, Mathias %A Lyytikäinen, Leo-Pekka %A Nutile, Teresa %A Sedaghat, Sanaz %A Sorice, Rossella %A Tin, Adrienne %A Yang, Qiong %A Ahluwalia, Tarunveer S %A Arking, Dan E %A Bihlmeyer, Nathan A %A Böger, Carsten A %A Carroll, Robert J %A Chasman, Daniel I %A Cornelis, Marilyn C %A Dehghan, Abbas %A Faul, Jessica D %A Feitosa, Mary F %A Gambaro, Giovanni %A Gasparini, Paolo %A Giulianini, Franco %A Heid, Iris %A Huang, Jinyan %A Imboden, Medea %A Jackson, Anne U %A Jeff, Janina %A Jhun, Min A %A Katz, Ronit %A Kifley, Annette %A Kilpeläinen, Tuomas O %A Kumar, Ashish %A Laakso, Markku %A Li-Gao, Ruifang %A Lohman, Kurt %A Lu, Yingchang %A Mägi, Reedik %A Malerba, Giovanni %A Mihailov, Evelin %A Mohlke, Karen L %A Mook-Kanamori, Dennis O %A Robino, Antonietta %A Ruderfer, Douglas %A Salvi, Erika %A Schick, Ursula M %A Schulz, Christina-Alexandra %A Smith, Albert V %A Smith, Jennifer A %A Traglia, Michela %A Yerges-Armstrong, Laura M %A Zhao, Wei %A Goodarzi, Mark O %A Kraja, Aldi T %A Liu, Chunyu %A Wessel, Jennifer %A Boerwinkle, Eric %A Borecki, Ingrid B %A Bork-Jensen, Jette %A Bottinger, Erwin P %A Braga, Daniele %A Brandslund, Ivan %A Brody, Jennifer A %A Campbell, Archie %A Carey, David J %A Christensen, Cramer %A Coresh, Josef %A Crook, Errol %A Curhan, Gary C %A Cusi, Daniele %A de Boer, Ian H %A de Vries, Aiko P J %A Denny, Joshua C %A Devuyst, Olivier %A Dreisbach, Albert W %A Endlich, Karlhans %A Esko, Tõnu %A Franco, Oscar H %A Fulop, Tibor %A Gerhard, Glenn S %A Glümer, Charlotte %A Gottesman, Omri %A Grarup, Niels %A Gudnason, Vilmundur %A Harris, Tamara B %A Hayward, Caroline %A Hocking, Lynne %A Hofman, Albert %A Hu, Frank B %A Husemoen, Lise Lotte N %A Jackson, Rebecca D %A Jørgensen, Torben %A Jørgensen, Marit E %A Kähönen, Mika %A Kardia, Sharon L R %A König, Wolfgang %A Kooperberg, Charles %A Kriebel, Jennifer %A Launer, Lenore J %A Lauritzen, Torsten %A Lehtimäki, Terho %A Levy, Daniel %A Linksted, Pamela %A Linneberg, Allan %A Liu, Yongmei %A Loos, Ruth J F %A Lupo, Antonio %A Meisinger, Christine %A Melander, Olle %A Metspalu, Andres %A Mitchell, Paul %A Nauck, Matthias %A Nürnberg, Peter %A Orho-Melander, Marju %A Parsa, Afshin %A Pedersen, Oluf %A Peters, Annette %A Peters, Ulrike %A Polasek, Ozren %A Porteous, David %A Probst-Hensch, Nicole M %A Psaty, Bruce M %A Qi, Lu %A Raitakari, Olli T %A Reiner, Alex P %A Rettig, Rainer %A Ridker, Paul M %A Rivadeneira, Fernando %A Rossouw, Jacques E %A Schmidt, Frank %A Siscovick, David %A Soranzo, Nicole %A Strauch, Konstantin %A Toniolo, Daniela %A Turner, Stephen T %A Uitterlinden, André G %A Ulivi, Sheila %A Velayutham, Dinesh %A Völker, Uwe %A Völzke, Henry %A Waldenberger, Melanie %A Wang, Jie Jin %A Weir, David R %A Witte, Daniel %A Kuivaniemi, Helena %A Fox, Caroline S %A Franceschini, Nora %A Goessling, Wolfram %A Köttgen, Anna %A Chu, Audrey Y %X

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10(-7)), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10(-8) by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

%B J Am Soc Nephrol %8 2016 Dec 05 %G eng %R 10.1681/ASN.2016020131 %0 Journal Article %J PLoS One %D 2017 %T Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study. %A de Vries, Paul S %A Sabater-Lleal, Maria %A Chasman, Daniel I %A Trompet, Stella %A Ahluwalia, Tarunveer S %A Teumer, Alexander %A Kleber, Marcus E %A Chen, Ming-Huei %A Wang, Jie Jin %A Attia, John R %A Marioni, Riccardo E %A Steri, Maristella %A Weng, Lu-Chen %A Pool, Rene %A Grossmann, Vera %A Brody, Jennifer A %A Venturini, Cristina %A Tanaka, Toshiko %A Rose, Lynda M %A Oldmeadow, Christopher %A Mazur, Johanna %A Basu, Saonli %A Frånberg, Mattias %A Yang, Qiong %A Ligthart, Symen %A Hottenga, Jouke J %A Rumley, Ann %A Mulas, Antonella %A de Craen, Anton J M %A Grotevendt, Anne %A Taylor, Kent D %A Delgado, Graciela E %A Kifley, Annette %A Lopez, Lorna M %A Berentzen, Tina L %A Mangino, Massimo %A Bandinelli, Stefania %A Morrison, Alanna C %A Hamsten, Anders %A Tofler, Geoffrey %A de Maat, Moniek P M %A Draisma, Harmen H M %A Lowe, Gordon D %A Zoledziewska, Magdalena %A Sattar, Naveed %A Lackner, Karl J %A Völker, Uwe %A McKnight, Barbara %A Huang, Jie %A Holliday, Elizabeth G %A McEvoy, Mark A %A Starr, John M %A Hysi, Pirro G %A Hernandez, Dena G %A Guan, Weihua %A Rivadeneira, Fernando %A McArdle, Wendy L %A Slagboom, P Eline %A Zeller, Tanja %A Psaty, Bruce M %A Uitterlinden, André G %A de Geus, Eco J C %A Stott, David J %A Binder, Harald %A Hofman, Albert %A Franco, Oscar H %A Rotter, Jerome I %A Ferrucci, Luigi %A Spector, Tim D %A Deary, Ian J %A März, Winfried %A Greinacher, Andreas %A Wild, Philipp S %A Cucca, Francesco %A Boomsma, Dorret I %A Watkins, Hugh %A Tang, Weihong %A Ridker, Paul M %A Jukema, Jan W %A Scott, Rodney J %A Mitchell, Paul %A Hansen, Torben %A O'Donnell, Christopher J %A Smith, Nicholas L %A Strachan, David P %A Dehghan, Abbas %X

An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5×10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5×10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.

%B PLoS One %V 12 %P e0167742 %8 2017 %G eng %N 1 %R 10.1371/journal.pone.0167742 %0 Journal Article %J Diabetes %D 2017 %T Genetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study. %A Sobrin, Lucia %A Chong, Yong He %A Fan, Qiao %A Gan, Alfred %A Stanwyck, Lynn K %A Kaidonis, Georgia %A Craig, Jamie E %A Kim, Jihye %A Liao, Wen-Ling %A Huang, Yu-Chuen %A Lee, Wen-Jane %A Hung, Yi-Jen %A Guo, Xiuqing %A Hai, Yang %A Ipp, Eli %A Pollack, Samuela %A Hancock, Heather %A Price, Alkes %A Penman, Alan %A Mitchell, Paul %A Liew, Gerald %A Smith, Albert V %A Gudnason, Vilmundur %A Tan, Gavin %A Klein, Barbara E K %A Kuo, Jane %A Li, Xiaohui %A Christiansen, Mark W %A Psaty, Bruce M %A Sandow, Kevin %A Jensen, Richard A %A Klein, Ronald %A Cotch, Mary Frances %A Wang, Jie Jin %A Jia, Yucheng %A Chen, Ching J %A Chen, Yii-Der Ida %A Rotter, Jerome I %A Tsai, Fuu-Jen %A Hanis, Craig L %A Burdon, Kathryn P %A Wong, Tien Yin %A Cheng, Ching-Yu %K Aged %K Diabetic Retinopathy %K Female %K Genome-Wide Association Study %K Humans %K Lipids %K Male %K Mendelian Randomization Analysis %K Middle Aged %K Polymorphism, Single Nucleotide %K Risk %X

Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.

%B Diabetes %V 66 %P 3130-3141 %8 2017 12 %G eng %N 12 %R 10.2337/db17-0398 %0 Journal Article %J Diabetes %D 2019 %T Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control. %A Pollack, Samuela %A Igo, Robert P %A Jensen, Richard A %A Christiansen, Mark %A Li, Xiaohui %A Cheng, Ching-Yu %A Ng, Maggie C Y %A Smith, Albert V %A Rossin, Elizabeth J %A Segrè, Ayellet V %A Davoudi, Samaneh %A Tan, Gavin S %A Chen, Yii-Der Ida %A Kuo, Jane Z %A Dimitrov, Latchezar M %A Stanwyck, Lynn K %A Meng, Weihua %A Hosseini, S Mohsen %A Imamura, Minako %A Nousome, Darryl %A Kim, Jihye %A Hai, Yang %A Jia, Yucheng %A Ahn, Jeeyun %A Leong, Aaron %A Shah, Kaanan %A Park, Kyu Hyung %A Guo, Xiuqing %A Ipp, Eli %A Taylor, Kent D %A Adler, Sharon G %A Sedor, John R %A Freedman, Barry I %A Lee, I-Te %A Sheu, Wayne H-H %A Kubo, Michiaki %A Takahashi, Atsushi %A Hadjadj, Samy %A Marre, Michel %A Trégouët, David-Alexandre %A McKean-Cowdin, Roberta %A Varma, Rohit %A McCarthy, Mark I %A Groop, Leif %A Ahlqvist, Emma %A Lyssenko, Valeriya %A Agardh, Elisabet %A Morris, Andrew %A Doney, Alex S F %A Colhoun, Helen M %A Toppila, Iiro %A Sandholm, Niina %A Groop, Per-Henrik %A Maeda, Shiro %A Hanis, Craig L %A Penman, Alan %A Chen, Ching J %A Hancock, Heather %A Mitchell, Paul %A Craig, Jamie E %A Chew, Emily Y %A Paterson, Andrew D %A Grassi, Michael A %A Palmer, Colin %A Bowden, Donald W %A Yaspan, Brian L %A Siscovick, David %A Cotch, Mary Frances %A Wang, Jie Jin %A Burdon, Kathryn P %A Wong, Tien Y %A Klein, Barbara E K %A Klein, Ronald %A Rotter, Jerome I %A Iyengar, Sudha K %A Price, Alkes L %A Sobrin, Lucia %X

To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts ( = 3,246) and seven African American cohorts ( = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a value <1 × 10 were investigated in replication cohorts that included 18,545 European, 16,453 Asian, and 2,710 Hispanic subjects. After correction for multiple testing, the C allele of rs142293996 in an intron of nuclear VCP-like () was associated with DR in European discovery cohorts ( = 2.1 × 10), but did not reach genome-wide significance after meta-analysis with replication cohorts. We applied the Disease Association Protein-Protein Link Evaluator (DAPPLE) to our discovery results to test for evidence of risk being spread across underlying molecular pathways. One protein-protein interaction network built from genes in regions associated with proliferative DR was found to have significant connectivity ( = 0.0009) and corroborated with gene set enrichment analyses. These findings suggest that genetic variation in as well as variation within a protein-protein interaction network that includes genes implicated in inflammation, may influence risk for DR.

%B Diabetes %V 68 %P 441-456 %8 2019 Feb %G eng %N 2 %R 10.2337/db18-0567 %0 Journal Article %J JAMA Ophthalmol %D 2020 %T Association of Genetic Variation With Keratoconus. %A McComish, Bennet J %A Sahebjada, Srujana %A Bykhovskaya, Yelena %A Willoughby, Colin E %A Richardson, Andrea J %A Tenen, Abi %A Charlesworth, Jac C %A Macgregor, Stuart %A Mitchell, Paul %A Lucas, Sionne E M %A Mills, Richard A %A Mackey, David A %A Li, Xiaohui %A Wang, Jie Jin %A Jensen, Richard A %A Rotter, Jerome I %A Taylor, Kent D %A Hewitt, Alex W %A Rabinowitz, Yaron S %A Baird, Paul N %A Craig, Jamie E %A Burdon, Kathryn P %K Adult %K Female %K Fuchs' Endothelial Dystrophy %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Keratoconus %K Lipase %K Logistic Models %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %X

Importance: Keratoconus is a condition in which the cornea progressively thins and protrudes in a conical shape, severely affecting refraction and vision. It is a major indication for corneal transplant. To discover new genetic loci associated with keratoconus and better understand the causative mechanism of this disease, we performed a genome-wide association study on patients with keratoconus.

Objective: To identify genetic susceptibility regions for keratoconus in the human genome.

Design, Setting, and Participants: This study was conducted with data from eye clinics in Australia, the United States, and Northern Ireland. The discovery cohort of individuals with keratoconus and control participants from Australia was genotyped using the Illumina HumanCoreExome single-nucleotide polymorphism array. After quality control and data cleaning, genotypes were imputed against the 1000 Genomes Project reference panel (phase III; version 5), and association analyses were completed using PLINK version 1.90. Single-nucleotide polymorphisms with P < 1.00 × 10-6 were assessed for replication in 3 additional cohorts. Control participants were drawn from the cohorts of the Blue Mountains Eye Study and a previous study of glaucoma. Replication cohorts were from a previous keratoconus genome-wide association study data set from the United States, a cohort of affected and control participants from Australia and Northern Ireland, and a case-control cohort from Victoria, Australia. Data were collected from January 2006 to March 2019.

Main Outcomes and Measures: Associations between keratoconus and 6 252 612 genetic variants were estimated using logistic regression after adjusting for ancestry using the first 3 principal components.

Results: The discovery cohort included 522 affected individuals and 655 control participants, while the replication cohorts included 818 affected individuals (222 from the United States, 331 from Australia and Northern Ireland, and 265 from Victoria, Australia) and 3858 control participants (2927 from the United States, 229 from Australia and Northern Ireland, and 702 from Victoria, Australia). Two novel loci reached genome-wide significance (defined as P < 5.00 × 10-8), with a P value of 7.46 × 10-9 at rs61876744 in patatin-like phospholipase domain-containing 2 gene (PNPLA2) on chromosome 11 and a P value of 6.35 × 10-12 at rs138380, 2.2 kb upstream of casein kinase I isoform epsilon gene (CSNK1E) on chromosome 22. One additional locus was identified with a P value less than 1.00 × 10-6 in mastermind-like transcriptional coactivator 2 (MAML2) on chromosome 11 (P = 3.91 × 10-7). The novel locus in PNPLA2 reached genome-wide significance in an analysis of all 4 cohorts (P = 2.45 × 10-8).

Conclusions and Relevance: In this relatively large keratoconus genome-wide association study, we identified a genome-wide significant locus for keratoconus in the region of PNPLA2 on chromosome 11.

%B JAMA Ophthalmol %V 138 %P 174-181 %8 2020 02 01 %G eng %N 2 %R 10.1001/jamaophthalmol.2019.5293