@article {6633, title = {Consistent directions of effect for established type 2 diabetes risk variants across populations: the population architecture using Genomics and Epidemiology (PAGE) Consortium.}, journal = {Diabetes}, volume = {61}, year = {2012}, month = {2012 Jun}, pages = {1642-7}, abstract = {

Common genetic risk variants for type 2 diabetes (T2D) have primarily been identified in populations of European and Asian ancestry. We tested whether the direction of association with 20 T2D risk variants generalizes across six major racial/ethnic groups in the U.S. as part of the Population Architecture using Genomics and Epidemiology Consortium (16,235 diabetes case and 46,122 control subjects of European American, African American, Hispanic, East Asian, American Indian, and Native Hawaiian ancestry). The percentage of positive (odds ratio [OR] >1 for putative risk allele) associations ranged from 69\% in American Indians to 100\% in European Americans. Of the nine variants where we observed significant heterogeneity of effect by racial/ethnic group (P(heterogeneity) < 0.05), eight were positively associated with risk (OR >1) in at least five groups. The marked directional consistency of association observed for most genetic variants across populations implies a shared functional common variant in each region. Fine-mapping of all loci will be required to reveal markers of risk that are important within and across populations.

}, keywords = {Adult, Aged, Aged, 80 and over, Alleles, Diabetes Mellitus, Type 2, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Metagenomics, Middle Aged, Population Groups, Risk, Risk Factors}, issn = {1939-327X}, doi = {10.2337/db11-1296}, author = {Haiman, Christopher A and Fesinmeyer, Megan D and Spencer, Kylee L and B{\r u}zkov{\'a}, Petra and Voruganti, V Saroja and Wan, Peggy and Haessler, Jeff and Franceschini, Nora and Monroe, Kristine R and Howard, Barbara V and Jackson, Rebecca D and Florez, Jose C and Kolonel, Laurence N and Buyske, Steven and Goodloe, Robert J and Liu, Simin and Manson, JoAnn E and Meigs, James B and Waters, Kevin and Mukamal, Kenneth J and Pendergrass, Sarah A and Shrader, Peter and Wilkens, Lynne R and Hindorff, Lucia A and Ambite, Jose Luis and North, Kari E and Peters, Ulrike and Crawford, Dana C and Le Marchand, Lo{\"\i}c and Pankow, James S} } @article {6827, title = {Association of functional polymorphism rs2231142 (Q141K) in the ABCG2 gene with serum uric acid and gout in 4 US populations: the PAGE Study.}, journal = {Am J Epidemiol}, volume = {177}, year = {2013}, month = {2013 May 1}, pages = {923-32}, abstract = {

A loss-of-function mutation (Q141K, rs2231142) in the ATP-binding cassette, subfamily G, member 2 gene (ABCG2) has been shown to be associated with serum uric acid levels and gout in Asians, Europeans, and European and African Americans; however, less is known about these associations in other populations. Rs2231142 was genotyped in 22,734 European Americans, 9,720 African Americans, 3,849 Mexican Americans, and 3,550 American Indians in the Population Architecture using Genomics and Epidemiology (PAGE) Study (2008-2012). Rs2231142 was significantly associated with serum uric acid levels (P = 2.37 {\texttimes} 10(-67), P = 3.98 {\texttimes} 10(-5), P = 6.97 {\texttimes} 10(-9), and P = 5.33 {\texttimes} 10(-4) in European Americans, African Americans, Mexican Americans, and American Indians, respectively) and gout (P = 2.83 {\texttimes} 10(-10), P = 0.01, and P = 0.01 in European Americans, African Americans, and Mexican Americans, respectively). Overall, the T allele was associated with a 0.24-mg/dL increase in serum uric acid level (P = 1.37 {\texttimes} 10(-80)) and a 1.75-fold increase in the odds of gout (P = 1.09 {\texttimes} 10(-12)). The association between rs2231142 and serum uric acid was significantly stronger in men, postmenopausal women, and hormone therapy users compared with their counterparts. The association with gout was also significantly stronger in men than in women. These results highlight a possible role of sex hormones in the regulation of ABCG2 urate transporter and its potential implications for the prevention, diagnosis, and treatment of hyperuricemia and gout.

}, keywords = {Adult, African Americans, Age Distribution, ATP-Binding Cassette Transporters, Comorbidity, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genetics, Population, Genome-Wide Association Study, Gout, Hormone Replacement Therapy, Humans, Indians, North American, Male, Mexican Americans, Middle Aged, Neoplasm Proteins, Polymorphism, Genetic, Postmenopause, Sex Distribution, United States, Uric Acid}, issn = {1476-6256}, doi = {10.1093/aje/kws330}, author = {Zhang, Lili and Spencer, Kylee L and Voruganti, V Saroja and Jorgensen, Neal W and Fornage, Myriam and Best, Lyle G and Brown-Gentry, Kristin D and Cole, Shelley A and Crawford, Dana C and Deelman, Ewa and Franceschini, Nora and Gaffo, Angelo L and Glenn, Kimberly R and Heiss, Gerardo and Jenny, Nancy S and K{\"o}ttgen, Anna and Li, Qiong and Liu, Kiang and Matise, Tara C and North, Kari E and Umans, Jason G and Kao, W H Linda} } @article {6065, title = {Effects of smoking on the genetic risk of obesity: the population architecture using genomics and epidemiology study.}, journal = {BMC Med Genet}, volume = {14}, year = {2013}, month = {2013 Jan 11}, pages = {6}, abstract = {

BACKGROUND: Although smoking behavior is known to affect body mass index (BMI), the potential for smoking to influence genetic associations with BMI is largely unexplored.

METHODS: As part of the {\textquoteright}Population Architecture using Genomics and Epidemiology (PAGE){\textquoteright} Consortium, we investigated interaction between genetic risk factors associated with BMI and smoking for 10 single nucleotide polymorphisms (SNPs) previously identified in genome-wide association studies. We included 6 studies with a total of 56,466 subjects (16,750 African Americans (AA) and 39,716 European Americans (EA)). We assessed effect modification by testing an interaction term for each SNP and smoking (current vs. former/never) in the linear regression and by stratified analyses.

RESULTS: We did not observe strong evidence for interactions and only observed two interactions with p-values <0.1: for rs6548238/TMEM18, the risk allele (C) was associated with BMI only among AA females who were former/never smokers (β = 0.018, p = 0.002), vs. current smokers (β = 0.001, p = 0.95, p(interaction) = 0.10). For rs9939609/FTO, the A allele was more strongly associated with BMI among current smoker EA females (β = 0.017, p = 3.5 x 10(-5)), vs. former/never smokers (β = 0.006, p = 0.05, p(interaction) = 0.08).

CONCLUSIONS: These analyses provide limited evidence that smoking status may modify genetic effects of previously identified genetic risk factors for BMI. Larger studies are needed to follow up our results.

CLINICAL TRIAL REGISTRATION: NCT00000611.

}, keywords = {Adolescent, Adult, African Americans, Aged, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Body Mass Index, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Humans, Male, Membrane Proteins, Middle Aged, Obesity, Polymorphism, Single Nucleotide, Proteins, Risk Factors, Smoking, Young Adult}, issn = {1471-2350}, doi = {10.1186/1471-2350-14-6}, author = {Fesinmeyer, Megan D and North, Kari E and Lim, Unhee and B{\r u}zkov{\'a}, Petra and Crawford, Dana C and Haessler, Jeffrey and Gross, Myron D and Fowke, Jay H and Goodloe, Robert and Love, Shelley-Ann and Graff, Misa and Carlson, Christopher S and Kuller, Lewis H and Matise, Tara C and Hong, Ching-Ping and Henderson, Brian E and Allen, Melissa and Rohde, Rebecca R and Mayo, Ping and Schnetz-Boutaud, Nathalie and Monroe, Kristine R and Ritchie, Marylyn D and Prentice, Ross L and Kolonel, Lawrence N and Manson, JoAnn E and Pankow, James and Hindorff, Lucia A and Franceschini, Nora and Wilkens, Lynne R and Haiman, Christopher A and Le Marchand, Lo{\"\i}c and Peters, Ulrike} } @article {6626, title = {Fine Mapping and Identification of BMI Loci in African Americans.}, journal = {Am J Hum Genet}, volume = {93}, year = {2013}, month = {2013 Oct 3}, pages = {661-71}, abstract = {

Genome-wide association studies (GWASs) primarily performed in European-ancestry (EA) populations have identified numerous loci associated with body mass index (BMI). However, it is still unclear whether these GWAS loci can be generalized to other ethnic groups, such as African Americans (AAs). Furthermore, the putative functional variant or variants in these loci mostly remain under investigation. The overall lower linkage disequilibrium in AA compared to EA populations provides the opportunity to narrow in or fine-map these BMI-related loci. Therefore, we used the Metabochip to densely genotype and evaluate 21 BMI GWAS loci identified in EA studies in 29,151 AAs from the Population Architecture using Genomics and Epidemiology (PAGE) study. Eight of the 21 loci (SEC16B, TMEM18, ETV5, GNPDA2, TFAP2B, BDNF, FTO, and MC4R) were found to be associated with BMI in AAs at 5.8~{\texttimes} 10(-5). Within seven out of these eight loci, we found that, on average, a substantially smaller number of variants was correlated (r(2) > 0.5) with the most significant SNP in AA than in EA populations (16 versus 55). Conditional analyses revealed GNPDA2 harboring a potential additional independent signal. Moreover, Metabochip-wide discovery analyses revealed two BMI-related loci, BRE (rs116612809, p = 3.6~{\texttimes} 10(-8)) and DHX34 (rs4802349, p = 1.2~{\texttimes} 10(-7)), which were significant when adjustment was made for the total number of SNPs tested across the chip. These results demonstrate that fine mapping in AAs is a powerful approach for both narrowing in on the underlying causal variants in known loci and discovering BMI-related loci.

}, keywords = {Adult, African Americans, Aged, Aged, 80 and over, Body Mass Index, Female, Genetic Loci, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Genotype, Humans, Linkage Disequilibrium, Male, Middle Aged, Obesity, Polymorphism, Single Nucleotide, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.08.012}, author = {Gong, Jian and Schumacher, Fredrick and Lim, Unhee and Hindorff, Lucia A and Haessler, Jeff and Buyske, Steven and Carlson, Christopher S and Rosse, Stephanie and B{\r u}zkov{\'a}, Petra and Fornage, Myriam and Gross, Myron and Pankratz, Nathan and Pankow, James S and Schreiner, Pamela J and Cooper, Richard and Ehret, Georg and Gu, C Charles and Houston, Denise and Irvin, Marguerite R and Jackson, Rebecca and Kuller, Lew and Henderson, Brian and Cheng, Iona and Wilkens, Lynne and Leppert, Mark and Lewis, Cora E and Li, Rongling and Nguyen, Khanh-Dung H and Goodloe, Robert and Farber-Eger, Eric and Boston, Jonathan and Dilks, Holli H and Ritchie, Marylyn D and Fowke, Jay and Pooler, Loreall and Graff, Misa and Fernandez-Rhodes, Lindsay and Cochrane, Barbara and Boerwinkle, Eric and Kooperberg, Charles and Matise, Tara C and Le Marchand, Lo{\"\i}c and Crawford, Dana C and Haiman, Christopher A and North, Kari E and Peters, Ulrike} } @article {6289, title = {Generalization and dilution of association results from European GWAS in populations of non-European ancestry: the PAGE study.}, journal = {PLoS Biol}, volume = {11}, year = {2013}, month = {2013 Sep}, pages = {e1001661}, abstract = {

The vast majority of genome-wide association study (GWAS) findings reported to date are from populations with European Ancestry (EA), and it is not yet clear how broadly the genetic associations described will generalize to populations of diverse ancestry. The Population Architecture Using Genomics and Epidemiology (PAGE) study is a consortium of multi-ancestry, population-based studies formed with the objective of refining our understanding of the genetic architecture of common traits emerging from GWAS. In the present analysis of five common diseases and traits, including body mass index, type 2 diabetes, and lipid levels, we compare direction and magnitude of effects for GWAS-identified variants in multiple non-EA populations against EA findings. We demonstrate that, in all populations analyzed, a significant majority of GWAS-identified variants have allelic associations in the same direction as in EA, with none showing a statistically significant effect in the opposite direction, after adjustment for multiple testing. However, 25\% of tagSNPs identified in EA GWAS have significantly different effect sizes in at least one non-EA population, and these differential effects were most frequent in African Americans where all differential effects were diluted toward the null. We demonstrate that differential LD between tagSNPs and functional variants within populations contributes significantly to dilute effect sizes in this population. Although most variants identified from GWAS in EA populations generalize to all non-EA populations assessed, genetic models derived from GWAS findings in EA may generate spurious results in non-EA populations due to differential effect sizes. Regardless of the origin of the differential effects, caution should be exercised in applying any genetic risk prediction model based on tagSNPs outside of the ancestry group in which it was derived. Models based directly on functional variation may generalize more robustly, but the identification of functional variants remains challenging.

}, keywords = {African Americans, Asian Americans, Body Mass Index, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Hispanic Americans, Humans, Indians, North American, Lipids, Metagenomics, Oceanic Ancestry Group, Polymorphism, Single Nucleotide}, issn = {1545-7885}, doi = {10.1371/journal.pbio.1001661}, author = {Carlson, Christopher S and Matise, Tara C and North, Kari E and Haiman, Christopher A and Fesinmeyer, Megan D and Buyske, Steven and Schumacher, Fredrick R and Peters, Ulrike and Franceschini, Nora and Ritchie, Marylyn D and Duggan, David J and Spencer, Kylee L and Dumitrescu, Logan and Eaton, Charles B and Thomas, Fridtjof and Young, Alicia and Carty, Cara and Heiss, Gerardo and Le Marchand, Lo{\"\i}c and Crawford, Dana C and Hindorff, Lucia A and Kooperberg, Charles L} } @article {6631, title = {Genetic risk factors for BMI and obesity in an ethnically diverse population: results from the population architecture using genomics and epidemiology (PAGE) study.}, journal = {Obesity (Silver Spring)}, volume = {21}, year = {2013}, month = {2013 Apr}, pages = {835-46}, abstract = {

OBJECTIVE: Several genome-wide association studies (GWAS) have demonstrated that common genetic variants contribute to obesity. However, studies of this complex trait have focused on ancestrally European populations, despite the high prevalence of obesity in some minority groups.

DESIGN AND METHODS: As part of the "Population Architecture using Genomics and Epidemiology (PAGE)" Consortium, we investigated the association between 13 GWAS-identified single-nucleotide polymorphisms (SNPs) and BMI and obesity in 69,775 subjects, including 6,149 American Indians, 15,415 African-Americans, 2,438 East Asians, 7,346 Hispanics, 604 Pacific Islanders, and 37,823 European Americans. For the BMI-increasing allele of each SNP, we calculated β coefficients using linear regression (for BMI) and risk estimates using logistic regression (for obesity defined as BMI >= 30) followed by fixed-effects meta-analysis to combine results across PAGE sites. Analyses stratified by racial/ethnic group assumed an additive genetic model and were adjusted for age, sex, and current smoking. We defined "replicating SNPs" (in European Americans) and "generalizing SNPs" (in other racial/ethnic groups) as those associated with an allele frequency-specific increase in BMI.

RESULTS: By this definition, we replicated 9/13 SNP associations (5 out of 8 loci) in European Americans. We also generalized 8/13 SNP associations (5/8 loci) in East Asians, 7/13 (5/8 loci) in African Americans, 6/13 (4/8 loci) in Hispanics, 5/8 in Pacific Islanders (5/8 loci), and 5/9 (4/8 loci) in American Indians.

CONCLUSION: Linkage disequilibrium patterns suggest that tagSNPs selected for European Americans may not adequately tag causal variants in other ancestry groups. Accordingly, fine-mapping in large samples is needed to comprehensively explore these loci in diverse populations.

}, keywords = {Alleles, Body Mass Index, Ethnic Groups, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Metagenomics, Obesity, Phenotype, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1930-739X}, doi = {10.1002/oby.20268}, author = {Fesinmeyer, Megan D and North, Kari E and Ritchie, Marylyn D and Lim, Unhee and Franceschini, Nora and Wilkens, Lynne R and Gross, Myron D and B{\r u}zkov{\'a}, Petra and Glenn, Kimberly and Quibrera, P Miguel and Fernandez-Rhodes, Lindsay and Li, Qiong and Fowke, Jay H and Li, Rongling and Carlson, Christopher S and Prentice, Ross L and Kuller, Lewis H and Manson, JoAnn E and Matise, Tara C and Cole, Shelley A and Chen, Christina T L and Howard, Barbara V and Kolonel, Laurence N and Henderson, Brian E and Monroe, Kristine R and Crawford, Dana C and Hindorff, Lucia A and Buyske, Steven and Haiman, Christopher A and Le Marchand, Lo{\"\i}c and Peters, Ulrike} } @article {6094, title = {Lack of associations of ten candidate coronary heart disease risk genetic variants and subclinical atherosclerosis in four US populations: the Population Architecture using Genomics and Epidemiology (PAGE) study.}, journal = {Atherosclerosis}, volume = {228}, year = {2013}, month = {2013 Jun}, pages = {390-9}, abstract = {

BACKGROUND: A number of genetic variants have been discovered by recent genome-wide association studies for their associations with clinical coronary heart disease (CHD). However, it is unclear whether these variants are also associated with the development of CHD as measured by subclinical atherosclerosis phenotypes, ankle brachial index (ABI), carotid artery intima-media thickness (cIMT) and carotid plaque.

METHODS: Ten CHD risk single nucleotide polymorphisms (SNPs) were genotyped in individuals of European American (EA), African American (AA), American Indian (AI), and Mexican American (MA) ancestry in the Population Architecture using Genomics and Epidemiology (PAGE) study. In each individual study, we performed linear or logistic regression to examine population-specific associations between SNPs and ABI, common and internal cIMT, and plaque. The results from individual studies were meta-analyzed using a fixed effect inverse variance weighted model.

RESULTS: None of the ten SNPs was significantly associated with ABI and common or internal cIMT, after Bonferroni correction. In the sample of 13,337 EA, 3809 AA, and 5353 AI individuals with carotid plaque measurement, the GCKR SNP rs780094 was significantly associated with the presence of plaque in AI only (OR~=~1.32, 95\% confidence interval: 1.17, 1.49, P~=~1.08~{\texttimes}~10(-5)), but not in the other populations (P~=~0.90 in EA and P~=~0.99 in AA). A 9p21 region SNP, rs1333049, was nominally associated with plaque in EA (OR~=~1.07, P~=~0.02) and in AI (OR~=~1.10, P~=~0.05).

CONCLUSIONS: We identified a significant association between rs780094 and plaque in AI populations, which needs to be replicated in future studies. There was little evidence that the index CHD risk variants identified through genome-wide association studies in EA influence the development of CHD through subclinical atherosclerosis as assessed by cIMT and ABI across ancestries.

}, keywords = {African Americans, Aged, Ankle Brachial Index, Asymptomatic Diseases, Carotid Artery Diseases, Carotid Intima-Media Thickness, Coronary Disease, European Continental Ancestry Group, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Indians, North American, Linear Models, Logistic Models, Male, Mexican Americans, Middle Aged, Odds Ratio, Phenotype, Polymorphism, Single Nucleotide, Predictive Value of Tests, Risk Assessment, Risk Factors, United States}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2013.02.038}, author = {Zhang, Lili and B{\r u}zkov{\'a}, Petra and Wassel, Christina L and Roman, Mary J and North, Kari E and Crawford, Dana C and Boston, Jonathan and Brown-Gentry, Kristin D and Cole, Shelley A and Deelman, Ewa and Goodloe, Robert and Wilson, Sarah and Heiss, Gerardo and Jenny, Nancy S and Jorgensen, Neal W and Matise, Tara C and McClellan, Bob E and Nato, Alejandro Q and Ritchie, Marylyn D and Franceschini, Nora and Kao, W H Linda} } @article {6628, title = {A systematic mapping approach of 16q12.2/FTO and BMI in more than 20,000 African Americans narrows in on the underlying functional variation: results from the Population Architecture using Genomics and Epidemiology (PAGE) study.}, journal = {PLoS Genet}, volume = {9}, year = {2013}, month = {2013}, pages = {e1003171}, abstract = {

Genetic variants in intron 1 of the fat mass- and obesity-associated (FTO) gene have been consistently associated with body mass index (BMI) in Europeans. However, follow-up studies in African Americans (AA) have shown no support for some of the most consistently BMI-associated FTO index single nucleotide polymorphisms (SNPs). This is most likely explained by different race-specific linkage disequilibrium (LD) patterns and lower correlation overall in AA, which provides the opportunity to fine-map this region and narrow in on the functional variant. To comprehensively explore the 16q12.2/FTO locus and to search for second independent signals in the broader region, we fine-mapped a 646-kb region, encompassing the large FTO gene and the flanking gene RPGRIP1L by investigating a total of 3,756 variants (1,529 genotyped and 2,227 imputed variants) in 20,488 AAs across five studies. We observed associations between BMI and variants in the known FTO intron 1 locus: the SNP with the most significant p-value, rs56137030 (8.3 {\texttimes} 10(-6)) had not been highlighted in previous studies. While rs56137030was correlated at r(2)>0.5 with 103 SNPs in Europeans (including the GWAS index SNPs), this number was reduced to 28 SNPs in AA. Among rs56137030 and the 28 correlated SNPs, six were located within candidate intronic regulatory elements, including rs1421085, for which we predicted allele-specific binding affinity for the transcription factor CUX1, which has recently been implicated in the regulation of FTO. We did not find strong evidence for a second independent signal in the broader region. In summary, this large fine-mapping study in AA has substantially reduced the number of common alleles that are likely to be functional candidates of the known FTO locus. Importantly our study demonstrated that comprehensive fine-mapping in AA provides a powerful approach to narrow in on the functional candidate(s) underlying the initial GWAS findings in European populations.

}, keywords = {Adaptor Proteins, Signal Transducing, Adult, African Americans, Aged, Aged, 80 and over, Alleles, Body Mass Index, Chromosome Mapping, Continental Population Groups, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Metagenomics, Middle Aged, Obesity, Proteins}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1003171}, author = {Peters, Ulrike and North, Kari E and Sethupathy, Praveen and Buyske, Steve and Haessler, Jeff and Jiao, Shuo and Fesinmeyer, Megan D and Jackson, Rebecca D and Kuller, Lew H and Rajkovic, Aleksandar and Lim, Unhee and Cheng, Iona and Schumacher, Fred and Wilkens, Lynne and Li, Rongling and Monda, Keri and Ehret, Georg and Nguyen, Khanh-Dung H and Cooper, Richard and Lewis, Cora E and Leppert, Mark and Irvin, Marguerite R and Gu, C Charles and Houston, Denise and B{\r u}zkov{\'a}, Petra and Ritchie, Marylyn and Matise, Tara C and Le Marchand, Lo{\"\i}c and Hindorff, Lucia A and Crawford, Dana C and Haiman, Christopher A and Kooperberg, Charles} } @article {7019, title = {Genetic determinants of age-related macular degeneration in diverse populations from the PAGE study.}, journal = {Invest Ophthalmol Vis Sci}, volume = {55}, year = {2014}, month = {2014 Sep 9}, pages = {6839-50}, abstract = {

PURPOSE: Substantial progress has been made in identifying susceptibility variants for AMD in European populations; however, few studies have been conducted to understand the role these variants play in AMD risk in diverse populations. The present study aims to examine AMD risk across diverse populations in known and suspected AMD complement factor and lipid-related loci.

METHODS: Targeted genotyping was performed across study sites for AMD and lipid trait-associated single nucleotide polymorphism (SNPs). Genetic association tests were performed at individual sites and then meta-analyzed using logistic regression assuming an additive genetic model stratified by self-described race/ethnicity. Participants included cases with early or late AMD and controls with no signs of AMD as determined by fundus photography. Populations included in this study were European Americans, African Americans, Mexican Americans, and Singaporeans from the Population Architecture using Genomics and Epidemiology (PAGE) study.

RESULTS: Index variants of AMD, rs1061170 (CFH) and rs10490924 (ARMS2), were associated with AMD at P=3.05{\texttimes}10(-8) and P=6.36{\texttimes}10(-6), respectively, in European Americans. In general, none of the major AMD index variants generalized to our non-European populations with the exception of rs10490924 in Mexican Americans at an uncorrected P value<0.05. Four lipid-associated SNPS (LPL rs328, TRIB1 rs6987702, CETP rs1800775, and KCTD10/MVK rs2338104) were associated with AMD in African Americans and Mexican Americans (P<0.05), but these associations did not survive strict corrections for multiple testing.

CONCLUSIONS: While most associations did not generalize in the non-European populations, variants within lipid-related genes were found to be associated with AMD. This study highlights the need for larger well-powered studies in non-European populations.

}, keywords = {Adult, Aged, Aged, 80 and over, Complement Factor H, DNA, Ethnic Groups, Female, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Macular Degeneration, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Prevalence, Prospective Studies, Proteins, Risk Factors, United States}, issn = {1552-5783}, doi = {10.1167/iovs.14-14246}, author = {Restrepo, Nicole A and Spencer, Kylee L and Goodloe, Robert and Garrett, Tiana A and Heiss, Gerardo and B{\r u}zkov{\'a}, Petra and Jorgensen, Neal and Jensen, Richard A and Matise, Tara C and Hindorff, Lucia A and Klein, Barbara E K and Klein, Ronald and Wong, Tien Y and Cheng, Ching-Yu and Cornes, Belinda K and Tai, E-Shyong and Ritchie, Marylyn D and Haines, Jonathan L and Crawford, Dana C} }