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Transthyretin (TTR) is the precursor of the fibrils that compromise organ function in familial and sporadic systemic amyloidoses (ATTR). RNA-interference and anti-sense therapeutics targeting TTR hepatic transcription have been shown to reduce TTR amyloid formation. In the present study, we leveraged genetic and phenotypic information from the UK Biobank and transcriptomic profiles from the Genotype-Tissue Expression project to test the association of genetically regulated TTR gene expression with 7,149 traits assessed in 420,531 individuals. We conducted a multi-tissue analysis of TTR transcription and identified an association with a operational procedure related to bone fracture (p=5.46×10(−6)). Using tissue-specific TTR expression information, we demonstrated that the association is driven by the genetic regulation of TTR hepatic expression (odds ratio [OR] = 3.46, p = 9.51×10(−5)). Using the UK Biobank electronic health records (EHRs), we investigated the comorbidities affecting individuals undergoing this surgical procedure. Excluding bone fracture EHRs, we identified a pattern of health outcomes previously associated with ATTR manifestations. These included osteoarthritis (OR=3.18, p=9.18×10(−8)), carpal tunnel syndrome (OR=2.15, p=0.002), and a history of gastrointestinal diseases (OR=2.01, p=8.07×10(−4)). In conclusion, our study supports that TTR hepatic expression can affect health outcomes linked to physiological and pathological processes presumably related to the encoded protein.

Background Due to its large impact on human health, socio-economic status (SES) could at least partially influence the established association between obesity and coronavirus disease 2019 (COVID-19) severity. To estimate the independent effect of body size and SES on the clinical manifestations of COVID-19, we conducted a Mendelian randomization (MR) study. Methods Applying two-sample MR approaches, we evaluated the effects of body mass index (BMI, n = 322 154), waist circumference (WC, n = 234 069), hip circumference (n = 213 019) and waist–hip ratio (n = 210 088) with respect to three COVID-19 outcomes: severe respiratory COVID-19 (cases = 8779, controls = 1 000 875), hospitalized COVID-19 (cases = 17 992, controls = 1 810 493) and COVID-19 infection (cases = 87 870, controls = 2 210 804). Applying a multivariable MR (MVMR) approach, we estimated the effect of these anthropometric traits on COVID-19 outcomes accounting for the effect of SES assessed as household income (n = 286 301). Results BMI and WC were associated with severe respiratory COVID-19 [BMI: odds ratio (OR) = 1.51, CI = 1.24–1.84, P = 3.01e-05; WC: OR = 1.48, 95% CI = 1.15–1.91, P = 0.0019] and hospitalized COVID-19 (BMI: OR = 1.50, 95% CI = 1.32–1.72, P = 8.83e-10; WC: OR = 1.41, 95% CI = 1.20–1.67, P = 3.72e-05). Conversely, income was associated with lower odds of severe respiratory (OR = 0.70, 95% CI = 0.53–0.93, P = 0.015) and hospitalized COVID-19 (OR = 0.78, 95% CI = 0.66–0.92, P = 0.003). MVMR analyses showed that the effect of these obesity-related traits on increasing the odds of COVID-19 negative outcomes becomes null when accounting for income. Conversely, the association of income with lower odds of COVID-19 negative outcomes is not affected when including the anthropometric traits in the multivariable model. Conclusion Our findings indicate that SES contributes to the effect of obesity-related traits on COVID-19 severity and hospitalization.

To investigate cross-ancestry genetics of complex traits, we conducted a phenome-wide analysis of loci with heterogeneous effects across African, Admixed-American, Central/South Asian, East Asian, European and Middle Eastern participants of the UK Biobank (N = 441 331). Testing 843 phenotypes, we identified 82 independent genomic regions mapping variants showing genome-wide significant (GWS) associations (P

Evidence of how human evolution shaped the polygenicity of human traits and diseases has been extensively studied in populations of European descent. However, limited information is currently available about its impact on other ancestry groups. Here, we investigated how different evolutionary processes affected the common variant heritability of traits and diseases in East Asians. Leveraging genome-wide association statistics from the Biobank Japan (up to 158,284 participants), we assessed natural selection (negative and positive), archaic introgression from Neanderthal and Denisova, and several genomic functional categories with respect to the heritability of physiological and pathological conditions. Similar to reports in European descent populations, the heritability estimates for East Asian traits were ubiquitously enriched for negative selection annotations (false discovery rate, FDR q−105). In summary, our study provides the first evidence regarding the impact of evolutionary processes on the genetics of complex traits in worldwide populations, highlighting the specific contribution of Denisovan introgression in East Asian populations.

BackgroundTransthyretin (TTR) is a multi-function protein involved in the systemic transport of retinol and thyroxine. It also participates in the neuronal response to stress and proteolysis of few specific substrates. TTR is also the precursor of the fibrils that compromise organ function in the familial and sporadic systemic amyloidoses (ATTR). RNA-interference and anti-sense therapeutics targetingTTRhepatic transcription have been shown to reduce TTR amyloid formation. The goal of our study was to investigate the role of genetic regulation ofTTRtranscriptomic variation in human traits and diseases.Methods and FindingsWe leveraged genetic and phenotypic information from the UK Biobank and transcriptomic profiles from the GTEx (Genotype-Tissue Expression) project to test the association of genetically regulatedTTRgene expression with 7,149 traits assessed in 420,531 individuals. We conducted a joint multi-tissue analysis ofTTRtranscription regulation and identified an association with a specific operational procedure related to secondary open reduction of fracture of bone (p=5.46×10−6, false discovery rate q=0.039). Using tissue-specificTTR cisexpression quantitative trait loci, we demonstrated that the association is driven by the genetic regulation ofTTRhepatic expression (odds ratio [OR] = 3.46, 95% confidence interval [CI] = 1.85-6.44, p = 9.51×10−5). Although there is an established relationship of retinol and thyroxine abnormalities with bone loss and the risk of bone fracture, this is the first evidence of a possible effect ofTTRtranscriptomic regulation. Investigating the UK Biobank electronic health records available, we investigated the comorbidities affecting individuals undergoing the specific surgical procedure. Excluding medical codes related to bone fracture events, we identified a pattern of health outcomes that have been previously associated with ATTR manifestations. These included osteoarthritis (OR=3.18, 95%CI=1.93-4.25, p=9.18×10−8), carpal tunnel syndrome (OR=2.15, 95%CI=1.33-3.48, p=0.002), and a history of gastrointestinal diseases (OR=2.01, 95%CI=1.33-3.01, p=8.07×10−4).ConclusionsThe present study supports the notion thatTTRhepatic expression can affect health outcomes linked to physiological and pathological processes presumably related to the encoded protein. Our findings highlight how the integration of omics information and electronic health records can successfully dissect the complexity of multi-function proteins such as TTR.

BackgroundObesity has been associated with more severe clinical manifestations of coronavirus disease 2019 (COVID-19). However, this association can be affected by many correlates of these traits. Due to its large impact on human health, socioeconomic status (SES) could at least partially influence the association between obesity and COVID-19 severity. To estimate the independent effect of traits related to body size and SES on the clinical manifestations of COVID-19, we conducted a Mendelian randomization (MR) study analyzing the effect of obesity-related anthropometric traits on COVID-19 outcomes.MethodsApplying two-sample MR approaches, we evaluated the effects of body mass index (BMI), waist circumference (WC), hip circumference, (HIP) and waist-hip ratio (WHR) studied in up to 234,069 participants from the Genetic Investigation of ANthropometric Traits (GIANT) consortium with respect to three COVID-19 outcomes: severe respiratory COVID-19 (5,101 cases vs. 1,383,241 controls), hospitalized COVID-19 (9,986 cases vs. 1,877,672 controls), and COVID-19 infection (38,984 cases vs. 1,644,784 controls) obtained from the COVID-19 Host Genetics Initiative (HGI). Finally, to test the effect of SES using multivariable MR methods, we analyzed genetic data related to self-reported household income (HI) information from 286,301 UK Biobank (UKB) participants.ResultsBMI and WC were associated with severe respiratory COVID-19 (BMI: OR⍰=⍰1.68 p⍰=⍰0.0004; WC: OR⍰=⍰1.72, p⍰=⍰0.007) and COVID-19 hospitalization (BMI: OR=⍰1.62, p⍰=⍰1.35e-06; WC: OR⍰=⍰1.62, p⍰=⍰0.0001). Also, HIP influenced hospitalized COVID-19 (OR⍰=⍰1.31, p⍰=⍰0.012) and COVID-19 infection (OR⍰=⍰1.18, p⍰=⍰0.002). Conversely, HI was associated with lower odds of severe respiratory COVID-19 (OR⍰=⍰0.57, p⍰=⍰0.011) and hospitalized COVID-19 (OR⍰=⍰0.71, p⍰=⍰0.045). Testing these effects in multivariable MR models, we observed that the effect of these obesity-related anthropometric traits on COVID-19 outcomes is not independent of SES effect assessed as HI.ConclusionsOur findings indicate that low SES is a contributor to the observed association between body size and COVID-19 outcomes.

Background: 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, peripheral edema, and several other noncardiac phenotypes such as carpal tunnel syndrome, and arthroplasty which are top reasons for ambulatory/outpatient surgeries (OSs) in the country. Methods: We conducted first-ever epigenome-wide association study using the Illumina’s EPIC array, in Val122Ile carriers of African descent for heart disease and multiple OSs—an early disease indicator. Differential methylation across genome wide cytosine-phosphate guanine (CpG) sites was tested between carriers with and without heart disease and OS. Significant CpG sites were investigated for cis-mQTLs loci, followed by gene ontology and protein-protein interaction network. We also investigated the significant CpG sites in a secondary cohort of carriers for replication. Results: Five differentially methylated sites ( P ≤2.1×10 −8 ) in genes— FAM129B , SKI , WDR27 , GLS , and an intergenic site near RP11-550A5.2, and one differentially methylated region containing KCNA6 and GALNT3 ( P =1.1×10 −12 ) were associated with heart disease. For OS, we observe 4 sites—2 sites in UBE2E3 and SEC14L5 , and other 2 in intergenic regions ( P ≤1.8×10 −7 ) and 3 regions overlapping SH3D21 , EVA1B , LTB4R2 , and CIDEB ( P ≤3.9×10 −7 ). Functional protein-interaction module analysis identified ABCA1 ( P =0.001) for heart disease. Six cis-mQTLs were associated with one of the significant CpG sites ( FAM129B ; P =4.1×10 −24 ). We replicated 2 CpG sites (cg18546846 and cg06641417; P GLS , ABCA1 , FAM129B ); cardiac fibrosis ( SKI ); and muscle tissue regulation ( SKI , FAM129B ). Conclusions: These findings highlight the link between a complex amyloid circuit and diverse symptoms of Val122Ile.

BACKGROUND -: 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, peripheral edema, and several other non-cardiac phenotypes such as carpal tunnel syndrome, and arthroplasty which are top reasons for ambulatory/outpatient surgeries in the country. METHODS -: We conducted first-ever epigenome-wide association study using the Illumina’s EPIC array, in Val122Ile carriers of African descent for heart disease (HD) and multiple outpatient surgeries (OS) - an early disease indicator. Differential methylation across genome wide CpG sites was tested between carriers with and without HD and OS. Significant CpG sites were investigated for cis-mQTLs loci, followed by gene ontology and protein-protein interaction (PPI) network. We also investigated the significant CpG sites in a secondary cohort of carriers for replication. RESULTS -: 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 protein-interaction module analysis identified ABCA1 (p=0.001) for HD. 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

Transthyretin (TTR) is the precursor of the fibrils that compromise organ function in hereditary and sporadic systemic amyloidoses (ATTR). RNA-interference and anti-sense therapeutics targeting TTR hepatic transcription have been shown to reduce TTR amyloid formation. In the present study, we leveraged genetic and phenotypic information from the UK Biobank and transcriptomic profiles from the Genotype-Tissue Expression project to test the association of genetically regulated TTR gene expression with 7149 traits assessed in 420,531 individuals. We conducted a multi-tissue analysis of TTR transcription and identified an association with a operational procedure related to bone fracture (p = 5.46×10−6). Using tissue-specific TTR expression information, we demonstrated that the association is driven by the genetic regulation of TTR hepatic expression (odds ratio [OR] = 3.46, p = 9.51×10−5). Using the UK Biobank electronic health records (EHRs), we investigated the comorbidities affecting individuals undergoing this surgical procedure. Excluding bone fracture EHRs, we identified a pattern of health outcomes previously associated with ATTR manifestations. These included osteoarthritis (OR = 3.18, p = 9.18×10−8), carpal tunnel syndrome (OR = 2.15, p = .002), and a history of gastrointestinal diseases (OR = 2.01, p = 8.07×10−4). In conclusion, our study supports that TTR hepatic expression can affect health outcomes linked to physiological and pathological processes presumably related to the encoded protein.

To distinguish correlation from causation, we performedin-silicoanalyses of three COVID-19 outcomes (N>1,000,000). We show genetic correlation and putative causality with depressive symptoms, metformin use, and alcohol use. COVID-19 risk loci associated with several hematologic biomarkers. Comprehensive findings inform genetic contributions to COVID-19 epidemiology, molecular mechanisms, and risk factors.

To provide novel insight regarding the inter-population diversity of loci associated with complex traits, we integrated genome-wide data from UK Biobank (UKB) and 1,000 Genomes Project (1KG) data representative of the genetic diversity among worldwide populations. We investigated genome-wide data of 4,359 traits from 361,194 UKB participants of European descent. Using 1KG data, we explored the allele frequency differences and linkage disequilibrium (LD) structure of UKB genome-wide significant (GWS) loci across worldwide populations. Functional annotation data were used to identify regulatory elements and evaluate the tagging properties of GWS variants. No significant difference was observed in allele frequency between UKB and 1KG GBR (British in England and Scotland). Considering other population groups, we identified genome-wide significant alleles with frequencies different from what expected by chance: UKB vs. 1KG Europeans without GBR (rs74945666; allele=T [0.908 vs. 0.03], standing height pGWAS=1.48×10-17), UKB vs. 1KG African (rs556562; allele=A [0.942 vs. 0.083], platelet count pGWAS=4.84×10-15), UKB vs. 1KG Admixed Americans (rs1812378; allele=T [0.931 vs. 0.089], standing height pGWAS=4.23×10-12), UKB vs. 1KG East Asian (rs55881864; allele=T [0.911 vs. 0.001], monocyte count pGWAS=7.29×10-13), and UKB vs. South Asian (rs74945666; allele=T [0.908 vs. 0.061], standing height pGWAS=1.48×10-17). LD-structure analysis and computational prediction showed differences in how these alleles tag functional elements across human populations. In conclusion, the human diversity of certain GWS loci appear to be affected by local adaptation while in other cases the associations may be biased by residual population stratification.

The Transthyretin ( TTR ) Val122Ile mutation causes a rare life-threatening disorder attributable to amyloid deposition. This mutation is mainly present in people of African descent; carriers have an increased risk of congestive heart failure and several other non-cardiac phenotypes such as carpal tunnel syndrome, peripheral edema, and arthroplasty. Cardiac disease in Val122Ile carriers may not depend solely on this mutation and other uninvestigated factors could contribute to clinical heterogeneity. One possible mechanism is through DNA methylation, the addition of a methyl group on CG-dinucleotides, which can result in altered gene expression. We investigated methylation changes contributing to heart disease in Val122Ile carriers to identify non-TTR regulatory mechanisms. We investigated 96 Val122Ile carriers of genetically-confirmed African descent using the Illumina EPIC array, which covers 850,000 methylation sites across the genome. We found changes in five methylated sites associated with heart disease. These map to FAM129B, SKI, WDR27, GLS , and an intergenic site near RP11-550A5.2 (p=1.6 to 4.6e-8), and a methylated region containing KCNA6 and GALNT3 (p=1.1e-12). Weighted methylated sites mapped to PPI network analysis identified ABCA1 gene (p=0.001). We also found six cis-mQTLs associated with the FAM129B CpG site (p=4.1e-24 to 2.8e-14). We replicated two of the aforementioned CpG sites near RP11-550A5.2 (p=0.021) and in FAM129B (p=0.016) at nominal significance in a case-control analysis of confirmed cases of TTR amyloidosis. GLS encodes glutaminase, which catalyzes the conversion of glutamine to glutamate. Its expression is increased in amyloid-beta neurons and neurofibrillary tangles. ABCA1 regulates cholesterol transport and interacts with APOA1 and APP ; its dysregulation increases amyloid deposition. Increasing FAM129B expression improves the clearance of amyloid deposits and rescues hippocampal neurons from apoptosis. The SKI expression modulates TGF-beta , resulting in cardiac fibrosis. Of note, SKI and FAM129B together are involved in the regularion of various muscle tissues. Collectively, these findings suggest that a complex amyloid-related gene circuit could explain diverse symptoms in Val122Ile carriers.

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; pGLS, 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.

Hereditary transthyretin (TTR) amyloidosis (hATTR) is a rare life-threatening disorder caused by amyloidogenic coding mutations located in TTR gene. To understand the high phenotypic variability observed among carriers of TTR disease-causing mutations, we conducted an epigenome-wide association study (EWAS) assessing more than 700,000 methylation sites and testing epigenetic difference of TTR coding mutation carriers vs. non-carriers. We observed a significant methylation change at cg09097335 site located in Beta-secretase 2 (BACE2) gene (standardized regression coefficient = −0.60, p = 6.26 × 10–8). This gene is involved in a protein interaction network enriched for biological processes and molecular pathways related to amyloid-beta metabolism (Gene Ontology: 0050435, q = 0.007), amyloid fiber formation (Reactome HSA-977225, q = 0.008), and Alzheimer’s disease (KEGG hsa05010, q = 2.2 × 10–4). Additionally, TTR and BACE2 share APP (amyloid-beta precursor protein) as a validated protein interactor. Within TTR gene region, we observed that Val30Met disrupts a methylation site, cg13139646, causing a drastic hypomethylation in carriers of this amyloidogenic mutation (standardized regression coefficient = −2.18, p = 3.34 × 10–11). Cg13139646 showed co-methylation with cg19203115 (Pearson’s r2 = 0.32), which showed significant epigenetic differences between symptomatic and asymptomatic carriers of amyloidogenic mutations (standardized regression coefficient = −0.56, p = 8.6 × 10–4). In conclusion, we provide novel insights related to the molecular mechanisms involved in the complex heterogeneity of hATTR, highlighting the role of epigenetic regulation in this rare disorder.

Transthyretin (TTR) gene has a causal role in a hereditary form of amyloidosis (ATTRm) and is potentially involved in the risk of senile systemic amyloidosis (SSA). To understand the genetics of ATTRm and SSA, we conducted a phenome-wide association study of TTR gene in 361,194 participants of European descent testing coding and non-coding variants. Among the 382 clinically-relevant phenotypes tested, TTR non-coding variants were associated with 26 phenotypic traits after multiple testing correction. These included signs related to both ATTRm and SSA such as chronic ischaemic heart disease (rs140226130, p=2.00×10−6), heart failure (rs73956431, p=2.74×10−6), atrial fibrillation (rs10163755, p=4.63×10−6), dysphagia (rs2949506, p=3.95×10−6), intestine diseases (rs970866, p=7.14×10−6) and anxiety (rs554521234, p=8.85×10−6). Consistent results were observed for TTR disease-causing mutation Val122Ile (rs76992529) with respect to carpal tunnel syndrome (p=6.41×10−6) and mononeuropathies of upper limbs (p=1.22×10−5). Sex differences were also observed in line with ATTRm and SSA epidemiology. Additionally, we explored possible modifier genes related to TTR function, observing convergent associations of RBP4 variants with the clinical phenotypes associated with TTR locus. In conclusion, we provide novel insights regarding the molecular basis of ATTRm and SSA based on large-scale cohort, expanding our understanding of the phenotypic spectrum associated with TTR gene variation.

Microbes inhabit different anatomical sites of the human body including oral cavity, gut, and skin. A growing literature highlights how microbiome variation is associated with human health and disease. There is strong evidence of bidirectional communication between gut and brain mediated by neurotransmitters and microbial metabolites. Here, we review the potential involvement of microbes residing in the gut and in other body sites in the pathogenesis of eight neuropsychiatric disorders, discussing findings from animal and human studies. The data reported provide a comprehensive overview of the current state of the microbiome research in neuropsychiatry, including hypotheses about the mechanisms underlying the associations reported and the translational potential of probiotics and prebiotics.

Transthyretin (TTR) gene has a causal role in a hereditary form of amyloidosis (ATTRm) and is potentially involved in the risk of wild-type transthyretin amyloidosis (ATTRwt). To understand the genetics of ATTRm and ATTRwt, we conducted a phenome-wide association study of TTR gene in 361,194 participants of European descent testing coding and non-coding variants. Among the 382 clinically relevant phenotypes tested, TTR non-coding variants were associated with 26 phenotypic traits after multiple testing correction. These included signs related to both ATTRm and ATTRwt such as chronic ischaemic heart disease (rs140226130, p = 2.00 × 10−6), heart failure (rs73956431, p = 2.74 × 10−6), atrial fibrillation (rs10163755, p = 4.63 × 10−6), dysphagia (rs2949506, p = 3.95 × 10−6), intestine diseases (rs970866, p = 7.14 × 10−6) and anxiety (rs554521234, p = 8.85 × 10−6). Consistent results were observed for TTR disease-causing mutation Val122Ile (rs76992529) with respect to carpal tunnel syndrome (p = 6.41 × 10−6) and mononeuropathies of upper limbs (p = 1.22 × 10−5). Sex differences were also observed in line with ATTRm and ATTRwt epidemiology. Additionally, we explored possible modifier genes related to TTR function, observing convergent associations of RBP4 variants with the clinical phenotypes associated with TTR locus. In conclusion, we provide novel insights regarding the molecular basis of ATTRm and ATTRwt based on large-scale cohort, expanding our understanding of the phenotypic spectrum associated with TTR gene variation.

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.