Clinical spectrum of Transthyretin amyloidogenic mutations among diverse population origins.

PURPOSE: Coding mutations in the Transthyretin (TTR) gene cause a hereditary form of amyloidosis characterized by a complex genotype-phenotype correlation with limited information regarding differences among worldwide populations. METHODS: We compared 676 diverse individuals carrying TTR amyloidogenic mutations (rs138065384, Phe44Leu; rs730881165, Ala81Thr; rs121918074, His90Asn; rs76992529, Val122Ile) to 12,430 non-carriers matched by age, sex, and genetically-inferred ancestry to assess their clinical presentations across 1,693 outcomes derived from electronic health records in UK biobank. RESULTS: In individuals of African descent (AFR), Val122Ile mutation was linked to multiple outcomes related to the circulatory system (fold-enrichment = 2.96, p = 0.002) with the strongest associations being cardiac congenital anomalies (phecode 747.1, p = 0.003), endocarditis (phecode 420.3, p = 0.006), and cardiomyopathy (phecode 425, p = 0.007). In individuals of Central-South Asian descent (CSA), His90Asn mutation was associated with dermatologic outcomes (fold-enrichment = 28, p = 0.001). The same TTR mutation was linked to neoplasms in European-descent individuals (EUR, fold-enrichment = 3.09, p = 0.003). In EUR, Ala81Thr showed multiple associations with respiratory outcomes related (fold-enrichment = 3.61, p = 0.002), but the strongest association was with atrioventricular block (phecode 426.2, p = 2.81 × 10- 4). Additionally, the same mutation in East Asians (EAS) showed associations with endocrine-metabolic traits (fold-enrichment = 4.47, p = 0.003). In the cross-ancestry meta-analysis, Val122Ile mutation was associated with peripheral nerve disorders (phecode 351, p = 0.004) in addition to cardiac congenital anomalies (fold-enrichment = 6.94, p = 0.003). CONCLUSIONS: Overall, these findings highlight that TTR amyloidogenic mutations present ancestry-specific and ancestry-convergent associations related to a range of health domains. This supports the need to increase awareness regarding the range of outcomes associated with TTR mutations across worldwide populations to reduce misdiagnosis and delayed diagnosis of TTR-related amyloidosis.

Sex differences in the pleiotropy of hearing difficulty with imaging-derived phenotypes: a brain-wide investigation.

Hearing difficulty (HD) is one of the major health burdens in older adults. While aging-related changes in the peripheral auditory system play an important role, genetic variation associated with brain structure and function could also be involved in HD predisposition. We analyzed a large-scale HD genome-wide association study (GWAS; Ntotal = 501,825, 56% females) and GWAS data related to 3,935 brain imaging-derived phenotypes (IDPs) assessed in up to 33,224 individuals (52% females) using multiple magnetic resonance imaging modalities. To investigate HD pleiotropy with brain structure and function, we conducted genetic correlation, latent causal variable, Mendelian randomization, and multivariable generalized linear regression analyses. Additionally, we performed local genetic correlation and multi-trait colocalization analyses to identify genomic regions and loci implicated in the pleiotropic mechanisms shared between HD and brain IDPs. We observed a widespread genetic correlation of HD with 120 IDPs in females, 89 IDPs in males, and 171 IDPs in the sex-combined analysis. The latent causal variable analysis showed that some of these genetic correlations could be due to cause-effect relationships. For seven correlations, the causal effects were also confirmed by the Mendelian randomization approach: vessel volume→HD in the sex-combined analysis; hippocampus volume→HD, cerebellum grey matter volume→HD, primary visual cortex volume→HD, and HD→fluctuation amplitudes of node 46 in resting-state functional MRI dimensionality 100 in females; global mean thickness→HD and HD→mean orientation dispersion index in superior corona radiata in males. The local genetic correlation analysis identified 13 pleiotropic regions between HD and these seven IDPs. We also observed a colocalization signal for the rs13026575 variant between HD, primary visual cortex volume, and SPTBN1 transcriptomic regulation in females. Brain structure and function may have a role in the sex differences in HD predisposition via possible cause-effect relationships and shared regulatory mechanisms.

Modeling the longitudinal changes of ancestry diversity in the Million Veteran Program.

BACKGROUND: The Million Veteran Program (MVP) participants represent 100 years of US history, including significant social and demographic changes over time. Our study assessed two aspects of the MVP: (i) longitudinal changes in population diversity and (ii) how these changes can be accounted for in genome-wide association studies (GWAS). To investigate these aspects, we divided MVP participants into five birth cohorts (N-range = 123,888 [born from 1943 to 1947] to 136,699 [born from 1948 to 1953]). RESULTS: Ancestry groups were defined by (i) HARE (harmonized ancestry and race/ethnicity) and (ii) a random-forest clustering approach using the 1000 Genomes Project and the Human Genome Diversity Project (1kGP + HGDP) reference panels (77 world populations representing six continental groups). In these groups, we performed GWASs of height, a trait potentially affected by population stratification. Birth cohorts demonstrate important trends in ancestry diversity over time. More recent HARE-assigned Europeans, Africans, and Hispanics had lower European ancestry proportions than older birth cohorts (0.010 < Cohen's d < 0.259, p < 7.80 × 10-4). Conversely, HARE-assigned East Asians showed an increase in European ancestry proportion over time. In GWAS of height using HARE assignments, genomic inflation due to population stratification was prevalent across all birth cohorts (linkage disequilibrium score regression intercept = 1.08 ± 0.042). The 1kGP + HGDP-based ancestry assignment significantly reduced the population stratification (mean intercept reduction = 0.045 ± 0.007, p < 0.05) confounding in the GWAS statistics. CONCLUSIONS: This study provides a characterization of ancestry diversity of the MVP cohort over time and compares two strategies to infer genetically defined ancestry groups by assessing differences in controlling population stratification in genome-wide association studies.

Cross-ancestry genome-wide association studies identified heterogeneous loci associated with differences of allele frequency and regulome tagging between participants of European descent and other ancestry groups from the UK Biobank.

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 < 5 × 10-8) in the trans-ancestry meta-analysis and GWS heterogeneity among the ancestry-specific effects. These included (i) loci with GWS association in one ancestry and concordant but heterogeneous effects among the other ancestries and (ii) loci with a GWS association in one ancestry group and an experiment-wide significant discordant effect (P < 6.1 × 10-4) in at least another ancestry. Since the trans-ancestry GWS associations were mostly driven by the European ancestry sample size, we investigated the differences of the allele frequency (ΔAF) and linkage disequilibrium regulome tagging (ΔLD) between European populations and the other ancestries. Within loci with concordant effects, the degree of heterogeneity was associated with European-Middle Eastern ΔAF (P = 9.04 × 10-6) and ΔLD of European populations with respect to African, Admixed-American and Central/South Asian groups (P = 8.21 × 10-4, P = 7.17 × 10-4 and P = 2.16 × 10-3, respectively). Within loci with discordant effects, ΔAF and ΔLD of European populations with respect to African and Central/South Asian ancestries were associated with the degree of heterogeneity (ΔAF: P = 7.69 × 10-3 and P = 5.31 × 10-3, ΔLD: P = 0.016 and P = 2.65 × 10-4, respectively). Considering the traits associated with cross-ancestry heterogeneous loci, we observed enrichments for blood biomarkers (P = 5.7 × 10-35) and physical appearance (P = 1.38 × 10-4). This suggests that these specific phenotypic classes may present considerable cross-ancestry heterogeneity owing to large allele frequency and LD variation among worldwide populations.

Genetic liability to suicidal thoughts and behaviors and risk of suicide attempt in US military veterans: moderating effects of cumulative trauma burden.

BACKGROUND: Little is known about environmental factors that may influence associations between genetic liability to suicidality and suicidal behavior. METHODS: This study examined whether a suicidality polygenic risk score (PRS) derived from a large genome-wide association study (N = 122,935) was associated with suicide attempts in a population-based sample of European-American US military veterans (N = 1664; 92.5% male), and whether cumulative lifetime trauma exposure moderated this association. RESULTS: Eighty-five veterans (weighted 6.3%) reported a history of suicide attempt. After adjusting for sociodemographic and psychiatric characteristics, suicidality PRS was associated with lifetime suicide attempt (odds ratio 2.65; 95% CI 1.37-5.11). A significant suicidality PRS-by-trauma exposure interaction emerged, such that veterans with higher levels of suicidality PRS and greater trauma burden had the highest probability of lifetime suicide attempt (16.6%), whereas the probability of attempts was substantially lower among those with high suicidality PRS and low trauma exposure (1.4%). The PRS-by-trauma interaction effect was enriched for genes implicated in cellular and developmental processes, and nervous system development, with variants annotated to the DAB2 and SPNS2 genes, which are implicated in inflammatory processes. Drug repurposing analyses revealed upregulation of suicide gene-sets in the context of medrysone, a drug targeting chronic inflammation, and clofibrate, a triacylglyceride level lowering agent. CONCLUSION: Results suggest that genetic liability to suicidality is associated with increased risk of suicide attempt among veterans, particularly in the presence of high levels of cumulative trauma exposure. Additional research is warranted to investigate whether incorporation of genomic information may improve suicide prediction models.

Psychosocial moderators of polygenic risk for suicidal ideation: Results from a 7-year population-based, prospective cohort study of U.S. veterans.

Polygenic risk scores (PRS) may help inform the etiology of suicidal thoughts and behaviors. In this study, we evaluated whether a suicidality PRS derived from a large genome-wide association study (GWAS) of suicidality from the UK Biobank (N = 122,935) predicted suicidal ideation (SI) in a 7-year population-based, prospective cohort of European-American US veterans (N = 1326). Results revealed that 8.8% (n = 115) of veterans developed new-onset SI, 4.0% (n = 52) had chronic SI, 3.4% (n = 31) had remitted SI, and 83.8% (n = 1128) denied SI over the study period. Suicidality PRSstandardized was positively associated with chronic SI (relative risk ratio [RRR] = 4.54, 95% confidence interval [CI] = 1.01-20.48) and new-onset SI (RRR = 2.97, 95%CI = 1.22-7.23), and negatively associated with remitted SI (RRR = 0.12, 95% CI = 0.02-0.60). Among veterans with higher suicidality PRS, those with higher baseline dispositional optimism had a lower likelihood of chronic SI (RRR = 0.67, 95% CI = 0.49-0.91) and higher likelihood of remitted SI (RRR = 1.98, 95% CI = 1.18-3.31). Among veterans with higher suicidality PRS, those with higher baseline levels of social support were less likely to develop new-onset SI (RRR = 0.95, 95% CI = 0.92-0.99). These interaction effects were enriched for genes implicated in neuron recognition and development, while the PRS main effect was enriched for genes involved in mannosylation. Collectively, results of this study suggest that suicidality PRS is linked prospectively to symptomatic courses of SI, and that dispositional optimism and social support moderate these associations. Interventions targeting these modifiable psychosocial factors may help mitigate risk of SI in veterans with high polygenic risk for suicidality.

Using phenotype risk scores to enhance gene discovery for generalized anxiety disorder and posttraumatic stress disorder.

UK Biobank (UKB) is a key contributor in mental health genome-wide association studies (GWAS) but only ~31% of participants completed the Mental Health Questionnaire ("MHQ responders"). We predicted generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), and major depression symptoms using elastic net regression in the ~69% of UKB participants lacking MHQ data ("MHQ non-responders"; NTraining = 50%; NTest = 50%), maximizing the informative sample for these traits. MHQ responders were more likely to be female, from higher socioeconomic positions, and less anxious than non-responders. Genetic correlation of GAD and PTSD between MHQ responders and non-responders ranged from 0.636 to 1.08; both were predicted by polygenic scores generated from independent cohorts. In meta-analyses of GAD (N = 489,579) and PTSD (N = 497,803), we discovered many novel genomic risk loci (13 for GAD and 40 for PTSD). Transcriptomic analyses converged on altered regulation of prenatal dorsolateral prefrontal cortex in these disorders. Our results provide one roadmap by which sample size and statistical power may be improved for gene discovery of incompletely ascertained traits in the UKB and other biobanks with limited mental health assessment.

Genetically regulated multi-omics study for symptom clusters of posttraumatic stress disorder highlights pleiotropy with hematologic and cardio-metabolic traits.

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that may arise in response to severe traumatic event and is diagnosed based on three main symptom clusters (reexperiencing, avoidance, and hyperarousal) per the Diagnostic Manual of Mental Disorders (version DSM-IV-TR). In this study, we characterized the biological heterogeneity of PTSD symptom clusters by performing a multi-omics investigation integrating genetically regulated gene, splicing, and protein expression in dorsolateral prefrontal cortex tissue within a sample of US veterans enrolled in the Million Veteran Program (N total = 186,689). We identified 30 genes in 19 regions across the three PTSD symptom clusters. We found nine genes to have cell-type specific expression, and over-representation of miRNA-families - miR-148, 30, and 8. Gene-drug target prioritization approach highlighted cyclooxygenase and acetylcholine compounds. Next, we tested molecular-profile based phenome-wide impact of identified genes with respect to 1678 phenotypes derived from the Electronic Health Records of the Vanderbilt University biorepository (N = 70,439). Lastly, we tested for local genetic correlation across PTSD symptom clusters which highlighted metabolic (e.g., obesity, diabetes, vascular health) and laboratory traits (e.g., neutrophil, eosinophil, tau protein, creatinine kinase). Overall, this study finds comprehensive genomic evidence including clinical and regulatory profiles between PTSD, hematologic and cardiometabolic traits, that support comorbidities observed in epidemiologic studies of PTSD.

Denisovan and Neanderthal archaic introgression differentially impacted the genetics of complex traits in modern populations.

BACKGROUND: Introgression from extinct Neanderthal and Denisovan human species has been shown to contribute to the genetic pool of modern human populations and their phenotypic spectrum. Evidence of how Neanderthal introgression shaped the genetics of human traits and diseases has been extensively studied in populations of European descent, with signatures of admixture reported for instance in genes associated with pigmentation, immunity, and metabolic traits. However, limited information is currently available about the impact of archaic introgression on other ancestry groups. Additionally, to date, no study has been conducted with respect to the impact of Denisovan introgression on the health and disease of modern populations. Here, we compare the way evolutionary pressures shaped the genetics of complex traits in East Asian and European populations, and provide evidence of the impact of Denisovan introgression on the health of East Asian and Central/South Asian populations. RESULTS: Leveraging genome-wide association statistics from the Biobank Japan and UK Biobank, we assessed whether Denisovan and Neanderthal introgression together with other evolutionary genomic signatures were enriched for the heritability of physiological and pathological conditions in populations of East Asian and European descent. In EAS, Denisovan-introgressed loci were enriched for coronary artery disease heritability (1.69-fold enrichment, p=0.003). No enrichment for archaic introgression was observed in EUR. We also performed a phenome-wide association study of Denisovan and Neanderthal alleles in six ancestry groups available in the UK Biobank. In EAS, the Denisovan-introgressed SNP rs62391664 in the major histocompatibility complex region was associated with albumin/globulin ratio (beta=-0.17, p=3.57×10-7). Neanderthal-introgressed alleles were associated with psychiatric and cognitive traits in EAS (e.g., "No Bipolar or Depression"-rs79043717 beta=-1.5, p=1.1×10-7), and with blood biomarkers (e.g., alkaline phosphatase-rs11244089 beta=0.1, p=3.69×10-116) and red hair color (rs60733936 beta=-0.86, p=4.49×10-165) in EUR. In the other ancestry groups, Neanderthal alleles were associated with several traits, also including the use of certain medications (e.g., Central/South East Asia: indapamide - rs732632 beta=-2.38, p=5.22×10-7). CONCLUSIONS: Our study provides novel evidence regarding the impact of archaic introgression on the genetics of complex traits in worldwide populations, highlighting the specific contribution of Denisovan introgression in EAS populations.

Role of microbes in the pathogenesis of neuropsychiatric disorders.

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.

Ancient genomes from a rural site in Imperial Rome (1st-3rd cent. CE): a genetic junction in the Roman Empire.

BACKGROUND: Rome became the prosperous Capital of the Roman Empire through the political and military conquests of neighbouring areas. People were able to move Romeward modifying the Rome area's demographic structure. However, the genomic evidence for the population of one of the broadest Empires in antiquity has been sparse until recently. AIM: The genomic analysis of people buried in Quarto Cappello del Prete (QCP) necropolis was carried out to help elucidate the genomic structure of Imperial Rome inhabitants. SUBJECTS AND METHODS: We recruited twenty-five individuals from QCP for ancient DNA analysis through whole-genome sequencing. Multiple investigations were carried out to unveil the genetic components featuring in the studied samples and the community's putative demographic structure. RESULTS: We generated reliable whole-genome data for 7 samples surviving quality controls. The distribution of Imperial Romans from QCP partly overlaps with present-day Southern Mediterranean and Southern-Near Eastern populations. CONCLUSION: The genomic legacy with the south-eastern shores of the Mediterranean Sea and the Central and Western Northern-African coast funerary influence pave the way for considering people buried in QCP as resembling a Punic-derived human group.

How Does Diet Influence Our Lives? Evaluating the Relationship between Isotopic Signatures and Mortality Patterns in Italian Roman Imperial and Medieval Periods.

The present research investigates the relationship between dietary habits and mortality patterns in the Roman Imperial and Medieval periods. The reconstructions of population dynamics and subsistence strategies provide a fascinating source of information for understanding our history. This is particularly true given that the changes in social, economic, political, and religious aspects related to the transition from the Roman period to the Middle Ages have been widely discussed. We analyzed the isotopic and mortality patterns of 616 individuals from 18 archeological sites (the Medieval Latium sites of Colonna, Santa Severa, Allumiere, Cencelle, and 14 Medieval and Imperial funerary contexts from Rome) to compile a survivorship analysis. A semi-parametric approach was applied, suggesting variations in mortality patterns between sexes in the Roman period. Nitrogen isotopic signatures influenced mortality in both periods, showing a quadratic and a linear effect for Roman Imperial and Medieval populations, respectively. No influence of carbon isotopic signatures has been detected for Roman Imperial populations. Conversely, increased mortality risk for rising carbon isotopic values was observed in Medieval samples.

Phenome-wide association study of TTR and RBP4 genes in 361,194 individuals reveals novel insights in the genetics of hereditary and wildtype transthyretin amyloidoses.

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.

Mitochondrial variability in the Mediterranean area: a complex stage for human migrations.

CONTEXT: The Mediterranean area has always played a significant role in human dispersal due to the large number of migratory events contributing to shape the cultural features and the genetic pool of its populations. OBJECTIVE: This paper aims to review and diachronically describe the mitogenome variability in the Mediterranean population and the main demic diffusions that occurred in this area over time. METHODS: Frequency distributions of the leading mitochondrial haplogroups have been geographically and chronologically evaluated. The variability of U5b and K lineages has been focussed to broaden the knowledge of their genetic histories. RESULTS: The mitochondrial genetic makeup of Palaeolithic hunter-gatherers is poorly defined within the extant Mediterranean populations, since only a few traces of their genetic contribution are still detectable. The Neolithic lineages are more represented, suggesting that the Neolithic revolution had a marked effect on the peopling of the Mediterranean area. The largest effect, however, was provided by historical migrations. CONCLUSION: Although the mitogenome variability has been widely used to try and clarify the evolution of the Mediterranean genetic makeup throughout almost 50 000 years, it is necessary to collect whole genome data on both extinct and extant populations from this area to fully reconstruct and interpret the impact of multiple migratory waves and their cultural and genetic consequences on the structure of the Mediterranean populations.

Mitochondrial characterisation of two Spanish populations from the Vera and Bejar valleys (Central Spain).

This survey reports the mitochondrial data of two Spanish populations living in the Vera and Bejar valleys, on the opposite slopes of the Sierra de Gredos (Central Spain), which crosses Spain east to west. The aim of the study was to characterise the mitochondrial genetic pool of the Vera and Bejar populations to investigate a putative mitogenetic differentiation between them, evidence that would support the role of the Sierra de Gredos as a genetic barrier in their micro-evolutionary histories. Blood samples of 137 people (66 from Vera and 71 from Bejar) were collected and mtDNA hypervariable regions I and II (HVR-I and HVR-II) were dissected along with several mtDNA-coding region SNPs. The main European mitochondrial lineages have been found both in Vera and in Bejar, together with the typical African haplogroups L (in Vera) and U6 (in Bejar). FST value and the 95% credible regions calculated for haplogroup frequencies do not reveal genetic differentiation among the populations. Vera and Bejar contain an expected mitochondrial variability within them, but they do not seem to be genetically different from each other, leading us to conclude that the Sierra de Gredos is not a significant genetic barrier in their maternal genetic history.

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

BACKGROUND: Transthyretin (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. RESULTS: We 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). CONCLUSIONS: Genetically determined TTR expression varied across human populations. This might contribute to the genotype-phenotype correlation of TTR amyloidosis.

Traces of forgotten historical events in mountain communities in Central Italy: A genetic insight.

OBJECTIVES: Analysis of human genetic variation in mountain communities can shed light on the peopling of mountainous regions, perhaps revealing whether the remote geographic location spared them from outside invasion and preserved their gene pool from admixture. In this study, we created a model to assess genetic traces of historical events by reconstructing the paternal and maternal genetic history of seven small mountain villages in inland valleys of Central Italy. METHODS: The communities were selected for their geographic isolation, attested biodemographic stability, and documented history prior to the Roman conquest. We studied the genetic structure by analyzing two hypervariable segments (HVS-I and HVS-II) of the mtDNA D-loop and several informative single nucleotide polymorphisms (SNPs) of the mtDNA coding region in 346 individuals, in addition to 17 short tandem repeats (STRs) and Y-chromosome SNPs in 237 male individuals. RESULTS: For both uniparental markers, most of the haplogroups originated in Western Europe while some Near Eastern haplogroups were identified at low frequencies. However, there was an evident genetic similarity between the Central Italian samples and Near Eastern populations mainly in the male genetic pool. CONCLUSIONS: The samples highlight an overall European genetic pattern both for mtDNA and Y chromosome. Notwithstanding this scenario, Y chromosome haplogroup Q, a common paternal lineage in Central/Western Asia but almost Europe-wide absent, was found, suggesting that Central Italy could have hosted a settlement from Anatolia that might be supported by cultural, topographic and genetic evidence.

Functional variability of glutathione S-transferases in Basque populations.

OBJECTIVES: Glutathione S-transferases (GSTs) are enzymes involved in Phase II reactions. They play a key role in cellular detoxification. Various studies have shown that genes coding for the GST are highly polymorphic and some of these variants are directly associated with a decrease of enzyme activity making individuals more susceptible to different clinical phenotypes. The aim of this study is to investigate the genetic variability of GST genes among human populations. We have focused our attention on the polymorphic variants of the GSTA1, GSTM1, GSTO1, GSTO2, GSTP1, GSTT1, and GSTT2B genes. METHODS: These polymorphisms were analyzed in a whole sample of 151 individuals: 112 autochthonous Navarrese Basques, and 39 non-autochthonous Navarrese Basques. DNA extraction from plasma was performed by using the phenol:chloroform:isoamylic alcohol method. Genotyping of the gene polymorphisms was performed by PCR Multiplex and the PCR-RFLP method. We applied correspondence analysis and built frequency-maps to compare the genetic structure in worldwide populations. RESULTS: Our results were compared with data available on the Human Genome Diversity Project (HGDP) and on the 1,000 Genomes Project to obtain information on the functional variability of GSTs in Basques. Our data indicated that Basque communities showed a higher differentiation of certain functional GST variants (i.e., GSTM1-positive/null genotype, GSTP1*I105V, and GSTT2B*1/0) than other European and Mediterranean populations. CONCLUSIONS: This might account for epidemiological differences in the predisposition to diseases and drug response among Basques and could be used to design and interpret genetic association studies for this particular population.

Distribution of the C9orf72 hexanucleotide repeat expansion in healthy subjects: a multicenter study promoted by the Italian IRCCS network of neuroscience and neurorehabilitation.

Introduction: High repeat expansion (HRE) alleles in C9orf72 have been linked to both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); ranges for intermediate allelic expansions have not been defined yet, and clinical interpretation of molecular data lacks a defined genotype-phenotype association. In this study, we provide results from a large multicenter epidemiological study reporting the distribution of C9orf72 repeats in healthy elderly from the Italian population. Methods: A total of 967 samples were collected from neurologically evaluated healthy individuals over 70 years of age in the 13 institutes participating in the RIN (IRCCS Network of Neuroscience and Neurorehabilitation) based in Italy. All samples were genotyped using the AmplideXPCR/CE C9orf72 Kit (Asuragen, Inc.), using standardized protocols that have been validated through blind proficiency testing. Results: All samples carried hexanucleotide G4C2 expansion alleles in the normal range. All samples were characterized by alleles with less than 25 repeats. In particular, 93.7% of samples showed a number of repeats ≤10, 99.9% ≤20 repeats, and 100% ≤25 repeats. Conclusion: This study describes the distribution of hexanucleotide G4C2 expansion alleles in an Italian healthy population, providing a definition of alleles associated with the neurological healthy phenotype. Moreover, this study provides an effective model of federation between institutes, highlighting the importance of sharing genomic data and standardizing analysis techniques, promoting translational research. Data derived from the study may improve genetic counseling and future studies on ALS/FTD.

Phenotype versus genotype methods for copy number variant analysis of glutathione S-transferases M1.

Several variants have been identified for genes encoding Glutathione S-transferase (GST) enzymes; some are associated with significant alteration of protein function. One of the most extensively studied is a copy number variant (CNV) in the GSTM1 gene. In this study, we compared phenotype (positive, null) and genotype (1/1, 1/0, 0/0) methods in order to assess dissimilarities obtained using these two different approaches to evaluate possible methodology-related bias. We analyzed a sample of 1947 individuals belonging to 18 human populations with different ethnic origins. We also evaluated whether the presence of missense substitutions in the GSTM1 gene might influence the association of the CNV with phenotype distribution. Through the comparison of GSTM1 CNV frequencies in phenotype and genotype among human populations, we observed that differences increase in high heterogeneous populations. Furthermore, we identified two missense variants (rs199816990 and rs202002774) that may distort the outcome of genetic association studies on Asian populations. These results indicate that the phenotype analysis may strongly alter the genetic association. Therefore, genotype discrimination analysis should be used to analyze GSTM1 CNV. To understand the role of GSTM1 in human health, the analysis of CNV should be combined with the investigation of single nucleotide polymorphisms with functional effect.