TY - JOUR T1 - Insights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis. JF - PLoS One Y1 - 2013 A1 - Holliday, Elizabeth G A1 - Smith, Albert V A1 - Cornes, Belinda K A1 - Buitendijk, Gabriëlle H S A1 - Jensen, Richard A A1 - Sim, Xueling A1 - Aspelund, Thor A1 - Aung, Tin A1 - Baird, Paul N A1 - Boerwinkle, Eric A1 - Cheng, Ching Yu A1 - van Duijn, Cornelia M A1 - Eiriksdottir, Gudny A1 - Gudnason, Vilmundur A1 - Harris, Tamara A1 - Hewitt, Alex W A1 - Inouye, Michael A1 - Jonasson, Fridbert A1 - Klein, Barbara E K A1 - Launer, Lenore A1 - Li, Xiaohui A1 - Liew, Gerald A1 - Lumley, Thomas A1 - McElduff, Patrick A1 - McKnight, Barbara A1 - Mitchell, Paul A1 - Psaty, Bruce M A1 - Rochtchina, Elena A1 - Rotter, Jerome I A1 - Scott, Rodney J A1 - Tay, Wanting A1 - Taylor, Kent A1 - Teo, Yik Ying A1 - Uitterlinden, André G A1 - Viswanathan, Ananth A1 - Xie, Sophia A1 - Vingerling, Johannes R A1 - Klaver, Caroline C W A1 - Tai, E Shyong A1 - Siscovick, David A1 - Klein, Ronald A1 - Cotch, Mary Frances A1 - Wong, Tien Y A1 - Attia, John A1 - Wang, Jie Jin KW - Apolipoproteins E KW - Complement Factor H KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Kruppel-Like Transcription Factors KW - Macular Degeneration KW - Nerve Tissue Proteins KW - Polymorphism, Single Nucleotide KW - Proteins KW - Risk Factors KW - Zinc Finger Protein Gli3 AB -

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.

VL - 8 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23326517?dopt=Abstract ER - TY - JOUR T1 - Association of levels of fasting glucose and insulin with rare variants at the chromosome 11p11.2-MADD locus: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. JF - Circ Cardiovasc Genet Y1 - 2014 A1 - Cornes, Belinda K A1 - Brody, Jennifer A A1 - Nikpoor, Naghmeh A1 - Morrison, Alanna C A1 - Chu, Huan A1 - Ahn, Byung Soo A1 - Wang, Shuai A1 - Dauriz, Marco A1 - Barzilay, Joshua I A1 - Dupuis, Josée A1 - Florez, Jose C A1 - Coresh, Josef A1 - Gibbs, Richard A A1 - Kao, W H Linda A1 - Liu, Ching-Ti A1 - McKnight, Barbara A1 - Muzny, Donna A1 - Pankow, James S A1 - Reid, Jeffrey G A1 - White, Charles C A1 - Johnson, Andrew D A1 - Wong, Tien Y A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - Siscovick, David S A1 - Sladek, Robert A1 - Meigs, James B KW - Aged KW - Aged, 80 and over KW - Aging KW - Blood Glucose KW - Chromosomes, Human, Pair 11 KW - Cohort Studies KW - Death Domain Receptor Signaling Adaptor Proteins KW - Diabetes Mellitus, Type 2 KW - Fasting KW - Female KW - Gene Frequency KW - Genetic Variation KW - Genome-Wide Association Study KW - Genomics KW - Guanine Nucleotide Exchange Factors KW - Heart Diseases KW - Humans KW - Insulin KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Sequence Analysis, DNA AB -

BACKGROUND: Common variation at the 11p11.2 locus, encompassing MADD, ACP2, NR1H3, MYBPC3, and SPI1, has been associated in genome-wide association studies with fasting glucose and insulin (FI). In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study, we sequenced 5 gene regions at 11p11.2 to identify rare, potentially functional variants influencing fasting glucose or FI levels.

METHODS AND RESULTS: Sequencing (mean depth, 38×) across 16.1 kb in 3566 individuals without diabetes mellitus identified 653 variants, 79.9% of which were rare (minor allele frequency <1%) and novel. We analyzed rare variants in 5 gene regions with FI or fasting glucose using the sequence kernel association test. At NR1H3, 53 rare variants were jointly associated with FI (P=2.73×10(-3)); of these, 7 were predicted to have regulatory function and showed association with FI (P=1.28×10(-3)). Conditioning on 2 previously associated variants at MADD (rs7944584, rs10838687) did not attenuate this association, suggesting that there are >2 independent signals at 11p11.2. One predicted regulatory variant, chr11:47227430 (hg18; minor allele frequency=0.00068), contributed 20.6% to the overall sequence kernel association test score at NR1H3, lies in intron 2 of NR1H3, and is a predicted binding site for forkhead box A1 (FOXA1), a transcription factor associated with insulin regulation. In human HepG2 hepatoma cells, the rare chr11:47227430 A allele disrupted FOXA1 binding and reduced FOXA1-dependent transcriptional activity.

CONCLUSIONS: Sequencing at 11p11.2-NR1H3 identified rare variation associated with FI. One variant, chr11:47227430, seems to be functional, with the rare A allele reducing transcription factor FOXA1 binding and FOXA1-dependent transcriptional activity.

VL - 7 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24951664?dopt=Abstract ER - TY - JOUR T1 - Genetic determinants of age-related macular degeneration in diverse populations from the PAGE study. JF - Invest Ophthalmol Vis Sci Y1 - 2014 A1 - Restrepo, Nicole A A1 - Spencer, Kylee L A1 - Goodloe, Robert A1 - Garrett, Tiana A A1 - Heiss, Gerardo A1 - Bůzková, Petra A1 - Jorgensen, Neal A1 - Jensen, Richard A A1 - Matise, Tara C A1 - Hindorff, Lucia A A1 - Klein, Barbara E K A1 - Klein, Ronald A1 - Wong, Tien Y A1 - Cheng, Ching-Yu A1 - Cornes, Belinda K A1 - Tai, E-Shyong A1 - Ritchie, Marylyn D A1 - Haines, Jonathan L A1 - Crawford, Dana C KW - Adult KW - Aged KW - Aged, 80 and over KW - Complement Factor H KW - DNA KW - Ethnic Groups KW - Female KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genotype KW - Humans KW - Macular Degeneration KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Prevalence KW - Prospective Studies KW - Proteins KW - Risk Factors KW - United States AB -

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=3.05×10(-8) and P=6.36×10(-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.

VL - 55 IS - 10 ER - TY - JOUR T1 - Association of the IGF1 gene with fasting insulin levels. JF - Eur J Hum Genet Y1 - 2016 A1 - Willems, Sara M A1 - Cornes, Belinda K A1 - Brody, Jennifer A A1 - Morrison, Alanna C A1 - Lipovich, Leonard A1 - Dauriz, Marco A1 - Chen, Yuning A1 - Liu, Ching-Ti A1 - Rybin, Denis V A1 - Gibbs, Richard A A1 - Muzny, Donna A1 - Pankow, James S A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - Siscovick, David S A1 - Vasan, Ramachandran S A1 - Kaplan, Robert C A1 - Isaacs, Aaron A1 - Dupuis, Josée A1 - van Duijn, Cornelia M A1 - Meigs, James B AB -

Insulin-like growth factor 1 (IGF-I) has been associated with insulin resistance. Genome-wide association studies (GWASs) of fasting insulin (FI) identified single-nucleotide variants (SNVs) near the IGF1 gene, raising two hypotheses: (1) these associations are mediated by IGF-I levels and (2) these noncoding variants either tag other functional variants in the region or are directly functional. In our study, analyses including 5141 individuals from population-based cohorts suggest that FI associations near IGF1 are not mediated by IGF-I. Analyses of targeted sequencing data in 3539 individuals reveal a large number of novel rare variants at the IGF1 locus and show a FI association with a subset of rare nonsynonymous variants (PSKAT=5.7 × 10(-4)). Conditional analyses suggest that this association is partly explained by the GWAS signal and the presence of a residual independent rare variant effect (Pconditional=0.019). Annotation using ENCODE data suggests that the GWAS variants may have a direct functional role in insulin biology. In conclusion, our study provides insight into variation present at the IGF1 locus and into the genetic architecture underlying FI levels, suggesting that FI associations of SNVs near IGF1 are not mediated by IGF-I and suggesting a role for both rare nonsynonymous and common functional variants in insulin biology.

VL - 24 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26860063?dopt=Abstract ER -