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

Iorio, Andrea; Angelis, Flavio De; Girolamo, Marco Di; Luigetti, Marco; Pradotto, Luca; Mazzeo, Anna; Frusconi, Sabrina; My, Filomena; Manfellotto, Dario; Fuciarelli, Maria; Polimanti, Renato

doi:10.1186/s12864-017-3646-1

Cited by 19 publications

(15 citation statements)

References 38 publications

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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: 55%

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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Section: Discussionsupporting

confidence: 55%

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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“…In a recent study, we observed that genetically determined TTR expression varies across human populations and this variation appears to be in line with known epidemiological differences in the patients affected. 21 On this basis, we evaluated the impact of the non-coding variants on the genetically determined TTR expression in Italian patients with TTR amyloidosis. Indeed, we hypothesize that non-coding variation regulating TTR gene expression in source and target tissues is one of the mechanisms involved in the phenotypic heterogeneity observed among the patients affected by TTR amyloidosis.…”

Section: Introductionmentioning

confidence: 99%

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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“…These epidemiological findings indicate that atypical phenotypes occurring earlier in life could be connected to the risk of heart failure in Val122Ile carriers. Findings from several studies including ours raise the possibility of non-regulatory molecular factors contributing to the genotype-phenotype correlation 10,[14][15][16][17] . Therefore, understanding the underlying biological changes in Val122Ile carriers is key to explaining the symptom heterogeneity and earlier onset of atypical phenotypes.…”

Section: Introductionmentioning

confidence: 72%

Epigenomic profiles of African American Transthyretin Val122Ile carriers reveals putatively dysregulated amyloid mechanisms

Pathak

Wendt

Lillo

et al. 2020

Preprint

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The Val122Ile mutation in Transthyretin (TTR) gene causes a rare, difficult to diagnose hereditary form of cardiac amyloidosis. This mutation is most common in the United States and mainly present in people of African descent. The carriers have an increased risk of congestive heart failure and several other non-cardiac phenotypes such as carpal tunnel syndrome, peripheral edema, and arthroplasty which are top reasons for ambulatory/outpatient surgeries in the country. We conducted first-ever epigenome-wide association study in Val122Ile carriers of African descent for heart disease (HD) and multiple outpatient surgeries (OS)- an early disease indicator. Five differentially methylated sites (p≤ ;2.1e-08) in genes FAM129B, SKI, WDR27, GLS, and an intergenic site near RP11-550A5.2 and one differentially methylated region containing KCNA6 and GALNT3 (p=1.1e-12) were associated with HD. For OS, we observe four sites, two sites in UBE2E3 and SEC14L5, and other two in intergenic regions (p ≤ ;1.8e-07) and three regions overlapping SH3D21, EVA1B, LTB4R2 and CIDEB (p ≤ ;3.9e-07). Functional PPI module analysis identified ABCA1 (p=0.001) for HS. Six cis-mQTLs were associated with one of the significant CpG sites (FAM129B; p=4.1e-24). We replicated two CpG sites (cg18546846 and cg06641417; p<0.05) in an external cohort of biopsy- confirmed cases of TTR amyloidosis. The genes identified are involved in transport and clearance of amyloid deposits (GLS, ABCA1, FAM129B); cardiac fibrosis (SKI); and muscle tissue regulation (SKI, FAM129B). These findings highlight the link between a complex amyloid circuit and diverse symptoms of Val122Ile.

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

Cited by 19 publications

References 38 publications

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

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

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

Epigenomic profiles of African American Transthyretin Val122Ile carriers reveals putatively dysregulated amyloid mechanisms

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