Dissection of genomewide-scan data in extended families reveals a major locus and oligogenic susceptibility for age-related macular degeneration

Iyengar, Sudha K.; Song, Danhong; Klein, Barbara E. K.; Klein, Ronald; Schick, James H.; Humphrey, Jennifer; Millard, Christopher; Liptak, Rachel; Russo, Karlie; Jun, Gyungah; Lee, Kristine E.; Fijal, Bonnie; Elston, Robert C.

doi:10.1016/j.ajo.2004.02.044

Cited by 27 publications

(58 citation statements)

References 53 publications

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“…One 5345Arg carrier (age 74 years at the time of diagnosis) was identified in the AMD cases (Schultz et al, 2003b). There are four hemicentin -1 SNPs that are reported (Iyengar et al, 2004). Among the four, rs1475113, rs743137 and rs680638 account for the majority of the linkage (Section 3).…”

Section: Amd-related Snps In Genes Associated With Monogenic Macular mentioning

confidence: 99%

“…Most recently, Iyengar et al (2004)reported a novel major AMD locus on chromosome 15q21 (GATA50C03/D15S659) with P = 2 × 10 -7 by dissecting genome-wide scan data of extended families and using a quantitative trait linkage approach. In this study, AMD was graded on a 16-level quantitative scale for severity based on drusen size, type, and area; pigmentary abnormalities; geographic atrophy; and signs of exudative macular degeneration.…”

Section: Amd Chromosomal Loci Identified By Linkage Studiesmentioning

confidence: 99%

“…Both hemicentin -1 and EFEMP1 encode extracellular matrix proteins that contain a series of calcium-binding epidermal growth factor-like domains followed by an unusual carboxy terminal EGF-like domain with eight cysteines. Iyengar et al (2004)followed linkage analysis of the extended families-based AMD cases with testing the sequence variation of hemicentin-1 in 1q31 linked families. Instead of finding any variation in exon 104 of hemicentin-1 , four hemicentin-1 SNPs (see Section 5), rs1475113 in intron 4, rs743137 in intron 36, hCV625089 in intron 86, and rs680638 in intron 105, were found to possibly be AMD related.…”

Section: Amd Chromosomal Loci Identified By Linkage Studiesmentioning

confidence: 99%

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Genetic factors of age-related macular degeneration

Tuo

Bojanowski

Chan

2004

Progress in Retinal and Eye Research

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Age-related macular degeneration (AMD) is a leading cause of blindness in the United States and developed countries. Although the etiology and pathogenesis of AMD remain unknown, a complex interaction of genetic and environmental factors is thought to exist. The incidence and progression of all of the features of AMD are known to increase significantly with age. The tendency for familial aggregation and the findings of gene variation association studies implicate a significant genetic component in the development of AMD. This review summarizes in detail the AMD-related genes identified by studies on genetically engineered and spontaneously gene-mutated (naturally mutated) animals, AMD chromosomal loci identified by linkage studies, AMD-related genes identified through studies of monogenic degenerative retinal diseases, and AMD-related gene variation identified by association studies.

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Section: Amd-related Snps In Genes Associated With Monogenic Macular mentioning

confidence: 99%

Section: Amd Chromosomal Loci Identified By Linkage Studiesmentioning

confidence: 99%

Section: Amd Chromosomal Loci Identified By Linkage Studiesmentioning

confidence: 99%

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Genetic factors of age-related macular degeneration

Tuo

Bojanowski

Chan

2004

Progress in Retinal and Eye Research

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“…Such an approach is almost identical to that of Iyenger et al 27 and can be implemented using SIBPAL. In theory, including SNPs for SHC3 as covariates during the linkage analysis effectively eliminates the contribution of the gene to the linkage signal.…”

Section: Human Study Populationmentioning

confidence: 99%

Linkage and association studies in African- and Caucasian-American populations demonstrate that SHC3 is a novel susceptibility locus for nicotine dependence

Sun

Lou

et al. 2006

Mol Psychiatry

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Our previous linkage study demonstrated that the 9q22-q23 chromosome region showed a 'suggestive' linkage to nicotine dependence (ND) in the Framingham Heart Study population. In this study, we provide further evidence for the linkage of this region to ND in an independent sample. Within this region, the gene encoding Src homology 2 domain-containing transforming protein C3 (SHC3) represents a plausible candidate for association with ND, assessed by smoking quantity (SQ), the Heaviness of Smoking Index (HSI) and the Fagerströ m Test for ND (FTND). We utilized 11 single-nucleotide polymorphisms within SHC3 to examine the association with ND in 602 nuclear families of either African-American (AA) or EuropeanAmerican (EA) origin. Individual SNP-based analysis indicated three SNPs for AAs and one for EAs were significantly associated with at least one ND measure. Haplotype analysis revealed that the haplotypes A-C-T-A-T-A of rs12519-rs3750399-rs4877042-rs2297313-rs1547696-rs1331188, with a frequency of 27.8 and 17.6%, and C-T-A-G-T of rs3750399-rs4877042-rs2297313-rs3818668-rs1547696, at a frequency of 44.7 and 30.6% in the AA and Combined samples, respectively, were significantly inversely associated with the ND measures. In the EA sample, another haplotype with a frequency of 10.6%, A-G-T-G of rs1331188-rs1556384-rs4534195-rs1411836, showed a significant inverse association with ND measures. These associations remained significant after Bonferroni correction. We further demonstrated the SHC3 contributed 40.1-59.2% (depending on the ND measures) of the linkage signals detected on chromosome 9. As further support, we found that nicotine administered through infusion increased the Shc3 mRNA level by 60% in the rat striatum, and decreased it by 22% in the nucleus accumbens (NA). At the protein level, Shc3 was decreased by 38.0% in the NA and showed no change in the striatum. Together, these findings strongly implicate SHC3 in the etiology of ND, which represents an important biological candidate for further investigation.

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“…Evidence for multiple loci with relatively small genetic effects can be obtained using a locus-counting method (Wiltshire et al 2002). This approach has been used in several studies (Caulfield et al 2003;Frayling et al 2003;Iyengar et al 2004aIyengar et al , 2004b to provide complementary evidence for linkage. In this approach, for a given LOD score, the number of independent regions of linkage (IRLs) expected under the null hypothesis of no linkage is determined by Monte Carlo simulation, and the number of independent linkage regions observed in the data is compared with this.…”

Section: Introductionmentioning

confidence: 99%

The effect of genotyping error in sib-pair genomewide linkage scans depends crucially upon the method of analysis

Walters¹

2005

J Hum Genet

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In genomewide linkage scans for complex diseases involving many loci with small genetic effects, it may be the case that no loci reach conventional statistical significance. A complementary method of evaluating linkage results, locus counting, may provide evidence for the existence of a number of genetic loci in these cases. Sib-pair study designs are often used in genomewide linkage scans, but because all genotype configurations are consistent with Mendelian inheritance, genotyping error will go largely undetected. Previous work on the effect of genotyping error has focused on a single disease locus. We considered the effect of two levels of genotyping error on genomewide evidence for linkage by using the simulated GAW 13 data. For affected sib-pair and non-parametric quantitative trait study designs, a 0.5% genotyping error rate reduced the number of independent linkage regions towards that expected under the null hypothesis of no linkage. A 2% genotyping error rate yielded less independent linkage regions than expected under the null hypothesis of no linkage. For a quantitative trait analysed using a parametric regressionbased method, there was very little erosion of the linkage signal, even for error rates as high as 2%.

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Dissection of genomewide-scan data in extended families reveals a major locus and oligogenic susceptibility for age-related macular degeneration

Cited by 27 publications

References 53 publications

Genetic factors of age-related macular degeneration

Genetic factors of age-related macular degeneration

Linkage and association studies in African- and Caucasian-American populations demonstrate that SHC3 is a novel susceptibility locus for nicotine dependence

The effect of genotyping error in sib-pair genomewide linkage scans depends crucially upon the method of analysis

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