Haplotype analysis of non-HLA immunogenetic loci in Turkish and worldwide populations

Karaca, Sefayet; Karaca, Mehmet; Civelek, Ersoy; Özgül, Rıza Köksal; Şekerel, Bülent Enis; Polimanti, Renato

doi:10.1016/j.gene.2016.04.050

Cited by 6 publications

(7 citation statements)

References 30 publications

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“…[15][16][17] Investigating the TTR haplotypic structure, we observed that the correlation between the Val30Met mutation and the ocular manifestation can be attributed to a specific Val30Met haplotype, which includes two regulatory non-coding variants. As also reported in genetic studies of different phenotypic traits, 38,39 the ocular manifestation in TTR amylodosis in our sample is due to a combination of the effects of a coding amylodogenic mutation and SNPs located in non-coding elements.…”

Section: Discussionsupporting

confidence: 82%

Non-coding variants contribute to the clinical heterogeneity of TTR amyloidosis

et al. 2017

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Coding mutations in TTR gene cause a rare hereditary form of systemic amyloidosis, which has a complex genotype-phenotype correlation. We investigated the role of non-coding variants in regulating TTR gene expression and consequently amyloidosis symptoms. We evaluated the genotype-phenotype correlation considering the clinical information of 129 Italian patients with TTR amyloidosis. Then, we conducted a re-sequencing of TTR gene to investigate how non-coding variants affect TTR expression and, consequently, phenotypic presentation in carriers of amyloidogenic mutations. Polygenic scores for genetically determined TTR expression were constructed using data from our re-sequencing analysis and the GTEx (Genotype-Tissue Expression) project. We confirmed a strong phenotypic heterogeneity across coding mutations causing TTR amyloidosis. Considering the effects of non-coding variants on TTR expression, we identified three patient clusters with specific expression patterns associated with certain phenotypic presentations, including late onset, autonomic neurological involvement, and gastrointestinal symptoms. This study provides novel data regarding the role of non-coding variation and the gene expression profiles in patients affected by TTR amyloidosis, also putting forth an approach that could be used to investigate the mechanisms at the basis of the genotype-phenotype correlation of the disease.

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Section: Discussionsupporting

confidence: 82%

Non-coding variants contribute to the clinical heterogeneity of TTR amyloidosis

et al. 2017

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“…These population clusters are an admixture of European, African, and Native American ancestry and a recent study indicated strong differences in the admixture proportions [32]. Previous studies demonstrated that haplotype structure of admixed populations play an important role in gene regulatory mechanisms [33, 34]. Our current data suggested that admixture differences could contribute to the heterogeneity observed among patients from admixed American populations.…”

Section: Discussionsupporting

confidence: 61%

Population diversity of the genetically determined TTR expression in human tissues and its implications in TTR amyloidosis

et al. 2017

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BackgroundTransthyretin (TTR) amyloidosis is a hereditary disease with a complex genotype-phenotype correlation. We conducted a literature survey to define the clinical landscape of TTR amyloidosis across populations worldwide. Then, we investigated whether the genetically determined TTR expression differs among human populations, contributing to the differences observed in patients. Polygenic scores for genetically determined TTR expression in 14 clinically relevant tissues were constructed using data from the GTEx (Genotype-Tissue Expression) project and tested in the samples from the 1,000 Genomes Project.ResultsWe observed differences among the ancestral groups and, to a lesser extent, among the investigated populations within the ancestry groups. Scandinavian populations differed in their genetically determined TTR expression of skeletal muscle tissue with respect to Southern Europeans (p = 6.79*10−6). This is in line with epidemiological data related to Swedish and Portuguese TTR Val30Met endemic areas. Familial amyloidotic cardiomyopathy (TTR deposits occur primarily in heart tissues) presents clinical variability among human populations, a finding that agrees with the among-ancestry diversity of genetically determined TTR expression in heart tissues (i.e., Atrial Appendage p = 4.55*10−28; Left Ventricle p = 6.54*10−35).ConclusionsGenetically determined TTR expression varied across human populations. This might contribute to the genotype-phenotype correlation of TTR amyloidosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-017-3646-1) contains supplementary material, which is available to authorized users.

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“…Furthermore, although those alleles are present in both AAs and EAs (MAF > 5%), we observed significant associations in the African-descent cohorts only. As also reported in other GWAS of substance use disorders [Smith et al, 2017], this may be due to the presence of epistatic interactions specific to African genomic background [Iorio et al, 2017; Karaca et al, 2016; Polimanti et al, 2015]. …”

Section: Discussionsupporting

confidence: 56%

Ancestry‐specific and sex‐specific risk alleles identified in a genome‐wide gene‐by‐alcohol dependence interaction study of risky sexual behaviors

Polimanti

Zhao

Farrer

et al. 2017

American J of Med Genetics Pt B

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We previously mapped loci for the genome-wide association studies (GWAS) and genome-wide gene-by-alcohol dependence interaction (GW-GxAD) analyses of risky sexual behaviors (RSB). This study extends those findings by analyzing the ancestry- and sex-specific AD-stratified effects on RSB. We examined the concordance of findings for the AD-stratified GWAS and the GW-GxAD analysis of RSB, with concordance defined as genome-wide significance in one analysis and at least nominal significance in the second analysis. 2,173 African-American (AA) and 1,751 European-American (EA) subjects were investigated. Information regarding RSB (lifetime experiences of unprotected sex and multiple sexual partners) and DSM-IV diagnosis of lifetime AD were derived from the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA). In our ancestry- and sex-specific analyses, we identified four independent genome-wide significant (GWS) loci (p<5*10−8) and one suggestive locus (p<6*10−8). In men, we observed a GWS signal in FAM162A (rs2002594, p=4.96*10−8). In women, there was a suggestive locus in PLGRKT (rs3824435, p=5.52*10−8). In AAs, there was a GWS signal in GRK5 (rs1316543, p=1.25*10−9). In AA men, we observed an intergenic GWS signal (rs12898370, p=4.49*10−8) near LINGO1. In EA men, there was a GWS signal in CCSER1 (rs62313897; p=7.93*10−10). The loci identified in this GWAS implicate molecular mechanisms related to psychiatric illness and personality features, suggesting that the interplay between AD and RSB is mediated by alleles associated with behavioral traits.

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Haplotype analysis of non-HLA immunogenetic loci in Turkish and worldwide populations

Cited by 6 publications

References 30 publications

Non-coding variants contribute to the clinical heterogeneity of TTR amyloidosis

Non-coding variants contribute to the clinical heterogeneity of TTR amyloidosis

Population diversity of the genetically determined TTR expression in human tissues and its implications in TTR amyloidosis

Ancestry‐specific and sex‐specific risk alleles identified in a genome‐wide gene‐by‐alcohol dependence interaction study of risky sexual behaviors

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