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Personality traits are summarized by five broad dimensions with pervasive influences on major life outcomes, strong links to psychiatric disorders and clear heritable components. To identify genetic variants associated with each of the five dimensions of personality we performed a genome-wide association (GWA) scan of 3972 individuals from a genetically isolated population within Sardinia, Italy. On the basis of the analyses of 362 129 single-nucleotide polymorphisms we found several strong signals within or near genes previously implicated in psychiatric disorders. They include the association of neuroticism with SNAP25 (rs362584, P=5 × 10−5), extraversion with BDNF and two cadherin genes (CDH13 and CDH23; Ps<5 × 10−5), openness with CNTNAP2 (rs10251794, P=3 × 10−5), agreeableness with CLOCK (rs6832769, P=9 × 10−6) and conscientiousness with DYRK1A (rs2835731, P=3 × 10−5). Effect sizes were small (less than 1% of variance), and most failed to replicate in the follow-up independent samples (N up to 3903), though the association between agreeableness and CLOCK was supported in two of three replication samples (overall P=2 × 10−5). We infer that a large number of loci may influence personality traits and disorders, requiring larger sample sizes for the GWA approach to confidently identify associated genetic variants. [ABSTRACT FROM AUTHOR]

Rainfall is generally accepted as one of the most important factors associated with an increased level of E. coli in bivalve molluscs. Performing microbiological risk assessment is relevant to official control authorities to determine the sanitary status of harvesting areas and, therefore, develop monitoring strategies and identify management practices that could be used to improve the quality and safety of the final product. The present study aimed to investigate the impact of rainfall on the content of E. coli in bivalve molluscs farmed in Sardinia (Italy). Enumeration of E. coli was performed according to the Most Probable Number (MPN) method (ISO 16649-3) on 1,920 bivalve samples collected from 7 regional counties between 2018 and 2020. Bivalve molluscs samples included 955 mussels (Mytilus galloprovincialis), 500 oysters (Crassostrea gigas), 325 clams (Ruditapes decussatus), 94 warty venus (Venus verrucosa), and 46 lagoon cockles (Cerastoderma glaucum). Rainfall data were obtained by the Department of Meteorology of the ARPA Sardegna. For each sampling site, GPS coordinates were used to identify gauge stations within catchment areas. Cumulative rain (mm) was recorded 1, 3, 5, 7, and 15 days before sampling, among which the 7-day cumulative rain was the strongest predictor of E. coli counts. Several thresholds of 7-day cumulative rain (from <10 mm up to >300 mm) before sampling were used to estimate the chances of a non-compliant sample (E. coli levels above the limit for sanitary class A; 230 MPN/100 g). The 7-day cumulative rain was positively associated with the chances of non-compliance. When the 7-day cumulative rain before sampling was >300 mm, 80.5 % of the samples were non-compliant, and the odds of a non-compliant sample were 23.6 times higher, as compared to samples harvested when the 7-day cumulative rainfall was <10 mm. Precipitation data could be a useful tool for interpreting anomalous results from official control authorities and reduce the costs that originate from closure of production areas., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We report genome-wide association study results for the levels of A1, A2 and fetal hemoglobins, analyzed for the first time concurrently. Integrating high-density array genotyping and whole-genome sequencing in a large general population cohort from Sardinia, we detected 23 associations at 10 loci. Five signals are due to variants at previously undetected loci: MPHOSPH9, PLTP-PCIF1, ZFPM1 (FOG1), NFIX and CCND3. Among the signals at known loci, ten are new lead variants and four are new independent signals. Half of all variants also showed pleiotropic associations with different hemoglobins, which further corroborated some of the detected associations and identified features of coordinated hemoglobin species production.

Background: Despite progress in identifying genes associated with breast cancer, many more risk loci exist. Genome-wide association analyses in genetically-homogeneous populations, such as that of Sardinia (Italy), could represent an additional approach to detect low penetrance alleles., Methods: We performed a genome-wide association study comparing 1431 Sardinian patients with non-familial, BRCA1/2-mutation-negative breast cancer to 2171 healthy Sardinian blood donors. DNA was genotyped using GeneChip Human Mapping 500 K Arrays or Genome-Wide Human SNP Arrays 6.0. To increase genomic coverage, genotypes of additional SNPs were imputed using data from HapMap Phase II. After quality control filtering of genotype data, 1367 cases (9 men) and 1658 controls (1156 men) were analyzed on a total of 2,067,645 SNPs., Results: Overall, 33 genomic regions (67 candidate SNPs) were associated with breast cancer risk at the p <  0(-6) level. Twenty of these regions contained defined genes, including one already associated with breast cancer risk: TOX3. With a lower threshold for preliminary significance to p < 10(-5), we identified 11 additional SNPs in FGFR2, a well-established breast cancer-associated gene. Ten candidate SNPs were selected, excluding those already associated with breast cancer, for technical validation as well as replication in 1668 samples from the same population. Only SNP rs345299, located in intron 1 of VAV3, remained suggestively associated (p-value, 1.16 x 10(-5)), but it did not associate with breast cancer risk in pooled data from two large, mixed-population cohorts., Conclusions: This study indicated the role of TOX3 and FGFR2 as breast cancer susceptibility genes in BRCA1/2-wild-type breast cancer patients from Sardinian population.

Objectives: Lower levels of serum brain derived neurotrophic factor (BDNF) is one of the best known biomarkers of depression. To identify genetic variants associated with serum BDNF, we tested the Val66Met (rs6265) functional variant and conducted a genome-wide association scan (GWAS)., Methods: In a community-based sample (N = 2054; aged 19-101, M = 51, SD = 15) from Sardinia, Italy, we measured serum BDNF concentration and conducted a GWAS., Results: We estimated the heritability of serum BDNF to be 0.48 from sib-pairs. There was no association between serum BDNF and Val66Met in the SardiNIA sample and in a meta-analysis of published studies (k = 13 studies, total n = 4727, P = 0.92). Although no genome-wide significant associations were identified, some evidence of association was found in the BDNF gene (rs11030102, P = 0.001) and at two loci (rs7170215, P = 4.8 × 10⁻⁵ and rs11073742 P = 1.2 × 10⁻⁵) near and within NTRK3 gene, a neurotrophic tyrosine kinase receptor., Conclusions: Our study and meta-analysis of the literature indicate that the BDNF Val66Met variant is not associated with serum BDNF, but other variants in the BDNF and NTRK3 genes might regulate the level of serum BDNF.

Objective: Personality traits related to high neuroticism and low conscientiousness are consistently associated with obesity. Hormones implicated in appetite and metabolism, such as leptin, may also be related to personality and may contribute to the association between these traits and obesity. The present research examined the association between leptin and Five Factor Model personality traits., Methods: A total of 5214 participants (58% women; mean [standard deviation] age = 44.42 [15.93] years; range, 18-94 years) from the SardiNIA project completed the Revised NEO Personality Inventory, a comprehensive measure of personality traits, and their blood samples were assayed for leptin., Results: As expected, lower conscientiousness was associated with higher circulating levels of leptin (r = -0.05, p < .001), even after controlling for body mass index, waist circumference, or inflammatory markers (r = -0.05, p < .001). Neuroticism, in contrast, was unrelated to leptin (r = 0.01, p = .31)., Conclusions: Individuals who are impulsive and lack discipline (low conscientiousness) may develop leptin resistance, which could be one factor that contributes to obesity, whereas the relation between a proneness to anxiety and depression (high neuroticism) and obesity may be mediated through other physiological and/or behavioral pathways.

Identifying the genes that influence levels of pro-inflammatory molecules can help to elucidate the mechanisms underlying this process. We first conducted a two-stage genome-wide association scan (GWAS) for the key inflammatory biomarkers Interleukin-6 (IL-6), the general measure of inflammation erythrocyte sedimentation rate (ESR), monocyte chemotactic protein-1 (MCP-1), and high-sensitivity C-reactive protein (hsCRP) in a large cohort of individuals from the founder population of Sardinia. By analysing 731,213 autosomal or X chromosome SNPs and an additional ∼1.9 million imputed variants in 4,694 individuals, we identified several SNPs associated with the selected quantitative trait loci (QTLs) and replicated all the top signals in an independent sample of 1,392 individuals from the same population. Next, to increase power to detect and resolve associations, we further genotyped the whole cohort (6,145 individuals) for 293,875 variants included on the ImmunoChip and MetaboChip custom arrays. Overall, our combined approach led to the identification of 9 genome-wide significant novel independent signals-5 of which were identified only with the custom arrays-and provided confirmatory evidence for an additional 7. Novel signals include: for IL-6, in the ABO gene (rs657152, p = 2.13×10(-29)); for ESR, at the HBB (rs4910472, p = 2.31×10(-11)) and UCN119B/SPPL3 (rs11829037, p = 8.91×10(-10)) loci; for MCP-1, near its receptor CCR2 (rs17141006, p = 7.53×10(-13)) and in CADM3 (rs3026968, p = 7.63×10(-13)); for hsCRP, within the CRP gene (rs3093077, p = 5.73×10(-21)), near DARC (rs3845624, p = 1.43×10(-10)), UNC119B/SPPL3 (rs11829037, p = 1.50×10(-14)), and ICOSLG/AIRE (rs113459440, p = 1.54×10(-08)) loci. Confirmatory evidence was found for IL-6 in the IL-6R gene (rs4129267); for ESR at CR1 (rs12567990) and TMEM57 (rs10903129); for MCP-1 at DARC (rs12075); and for hsCRP at CRP (rs1205), HNF1A (rs225918), and APOC-I (rs4420638). Our results improve the current knowledge of genetic variants underlying inflammation and provide novel clues for the understanding of the molecular mechanisms regulating this complex process., Competing Interests: The authors have declared that no competing interests exist.

The tendency to seek stimulating activities and intense sensations define excitement-seeking, a personality trait akin to some aspects of sensation-seeking. This trait is a central feature of extraversion and is a component of the multifaceted impulsivity construct. Those who score high on measures of excitement-seeking are more likely to smoke, use other drugs, gamble, drive recklessly, have unsafe/unprotected sex and engage in other risky behaviors of clinical and social relevance. To identify common genetic variants associated with the Excitement-Seeking scale of the Revised NEO Personality Inventory, we performed genome-wide association studies in six samples of European ancestry (N=7860), and combined the results in a meta-analysis. We identified a genome-wide significant association between the Excitement-Seeking scale and rs7600563 (P=2 × 10(-8)). This single-nucleotide polymorphism maps within the catenin cadherin-associated protein, alpha 2 (CTNNA2) gene, which encodes for a brain-expressed α-catenin critical for synaptic contact. The effect of rs7600563 was in the same direction in all six samples, but did not replicate in additional samples (N=5105). The results provide insight into the genetics of excitement-seeking and risk-taking, and are relevant to hyperactivity, substance use, antisocial and bipolar disorders.

Complex trait genome-wide association studies (GWAS) provide an efficient strategy for evaluating large numbers of common variants in large numbers of individuals and for identifying trait-associated variants. Nevertheless, GWAS often leave much of the trait heritability unexplained. We hypothesized that some of this unexplained heritability might be due to common and rare variants that reside in GWAS identified loci but lack appropriate proxies in modern genotyping arrays. To assess this hypothesis, we re-examined 7 genes (APOE, APOC1, APOC2, SORT1, LDLR, APOB, and PCSK9) in 5 loci associated with low-density lipoprotein cholesterol (LDL-C) in multiple GWAS. For each gene, we first catalogued genetic variation by re-sequencing 256 Sardinian individuals with extreme LDL-C values. Next, we genotyped variants identified by us and by the 1000 Genomes Project (totaling 3,277 SNPs) in 5,524 volunteers. We found that in one locus (PCSK9) the GWAS signal could be explained by a previously described low-frequency variant and that in three loci (PCSK9, APOE, and LDLR) there were additional variants independently associated with LDL-C, including a novel and rare LDLR variant that seems specific to Sardinians. Overall, this more detailed assessment of SNP variation in these loci increased estimates of the heritability of LDL-C accounted for by these genes from 3.1% to 6.5%. All association signals and the heritability estimates were successfully confirmed in a sample of ∼10,000 Finnish and Norwegian individuals. Our results thus suggest that focusing on variants accessible via GWAS can lead to clear underestimates of the trait heritability explained by a set of loci. Further, our results suggest that, as prelude to large-scale sequencing efforts, targeted re-sequencing efforts paired with large-scale genotyping will increase estimates of complex trait heritability explained by known loci., Competing Interests: The authors have declared that no competing interests exist.

Background: Independent of temporal circumstances, some individuals have greater susceptibility to depressive affects, such as feelings of guilt, sadness, hopelessness, and loneliness. Identifying the genetic variants that contribute to these individual differences can point to biological pathways etiologically involved in psychiatric disorders., Methods: Genome-wide association scans for the depression scale of the Revised NEO Personality Inventory in community-based samples from a genetically homogeneous area of Sardinia, Italy (n = 3972) and from the Baltimore Longitudinal Study of Aging in the United States (n = 839)., Results: Meta-analytic results for genotyped or imputed single nucleotide polymorphisms indicate that the strongest association signals for trait depression were found in RORA (rs12912233; p = 6 × 10⁻⁷), a gene involved in circadian rhythm. A plausible biological association was also found with single nucleotide polymorphisms within GRM8 (rs17864092; p = 5 × 10⁻⁶), a metabotropic receptor for glutamate, a major excitatory neurotransmitter in the central nervous system., Conclusions: These findings suggest shared genetic basis underlying the continuum from personality traits to psychopathology., (Published by Elsevier Inc.)

A large body of evidence links antagonism-related traits with cardiovascular outcomes, but less is known about how psychological traits are associated with intermediate markers of cardiovascular disease. Using a large, community-based sample from Sardinia, Italy (n=5614), this study examined how trait antagonism (low agreeableness) and its facets are associated with carotid artery intima-media thickness, a measure of arterial thickening. Controlling for demographic and cardiovascular risk factors, low agreeableness and, in particular, low straightforwardness and low compliance, were associated with greater carotid thickening, measured concurrently and prospectively, and with increases in intima-media thickness over 3 years. Indeed, those in the bottom 10% of agreeableness had a 40% increase in risk for elevated intima-media thickness. Although men have thicker arterial walls, women with antagonistic traits had similar carotid thickening as antagonistic men. Antagonistic individuals, especially those who are manipulative and aggressive, have greater increases in arterial thickening, independent of traditional cardiovascular risk factors.

Background: High Neuroticism and low Conscientiousness are frequently implicated in health-risk behaviors, such as smoking and overeating, as well as health outcomes, including mortality. Their associations with physiological markers of morbidity and mortality, such as inflammation, are less well documented. The present research examines the association between the five major dimensions of personality and interleukin-6 (IL-6), a pro-inflammatory cytokine often elevated in patients with chronic morbidity and frailty., Method: A population-based sample (n=4923) from four towns in Sardinia, Italy, had their levels of IL-6 measured and completed a comprehensive personality questionnaire, the NEO-PI-R. Analyses controlled for factors known to have an effect on IL-6: age; sex; smoking; weight; aspirin use; disease burden., Results: High Neuroticism and low Conscientiousness were both associated with higher levels of IL-6. The findings remained significant after controlling for the relevant covariates. Similar results were found for C-reactive protein, a related marker of chronic inflammation. Further, smoking and weight partially mediated the association between impulsivity-related traits and higher IL-6 levels. Finally, logistic regressions revealed that participants either in the top 10% of the distribution of Neuroticism or the bottom 10% of conscientiousness had an approximately 40% greater risk of exceeding clinically relevant thresholds of IL-6., Conclusions: Consistent with the literature on personality and self-reported health, individuals high on Neuroticism or low on Conscientiousness show elevated levels of this inflammatory cytokine. Identifying critical medical biomarkers associated with personality may help to elucidate the physiological mechanisms responsible for the observed connections between personality traits and physical health.

Unhealthy lipid levels are among the leading controllable risk factors for coronary heart disease. To identify the psychological factors associated with dyslipidemia, this study investigates the personality correlates of cholesterol (total, LDL, and HDL) and triglycerides. A community-based sample (N=5532) from Sardinia, Italy, had their cholesterol and triglyceride levels assessed and completed a comprehensive personality questionnaire, the NEO-PI-R. All analyses controlled for age, sex, BMI, smoking, drinking, hypertension, and diabetes. Low Conscientiousness and traits related to impulsivity were associated with lower HDL cholesterol and higher triglycerides. Compared to the lowest 10%, those who scored in top 10% on Impulsivity had a 2.5 times greater risk of exceeding the clinical threshold for elevated triglycerides (OR=2.51, CI=1.56-4.07). In addition, sex moderated the association between trait depression (a component of Neuroticism) and HDL cholesterol, such that trait depression was associated with lower levels of HDL cholesterol in women but not men. When considering the connection between personality and health, unhealthy lipid profiles may be one intermediate biomarker between personality and morbidity and mortality., (Published by Elsevier B.V.)

The polymorphism in the serotonin transporter gene promoter region (5-HTTLPR) is by far the most studied variant hypothesized to influence Neuroticism-related personality traits. The results of previous studies have been mixed and appear moderated by the personality questionnaire used. Studies that used the TCI to assess Harm Avoidance or the EPQ to assess Neuroticism have found no association with the 5-HTTLPR. However, studies that used the NEO-PI-R or related instruments (NEO-PI, NEO-FFI) to measure Neuroticism have found some evidence of association. This study examines the association of variants in the serotonin transporter gene in a sample from a genetically isolated population within Sardinia (Italy) that is several times larger than previous samples that used the NEO-PI-R (N = 3,913). The association was also tested in a sample (N = 548) from the Baltimore Longitudinal Study of Aging (BLSA), in which repeated NEO-PI-R assessments were obtained. In the SardiNIA sample, we found no significant association of the 5-HTTLPR genotypes with Neuroticism or its facets (Anxiety, Angry-Hostility, Depression, Self-Consciousness, Impulsiveness, and Vulnerability). In the BLSA sample, we found lower scores on Neuroticism traits for the heterozygous group, which is inconsistent with previous studies. We also examined eight SNPs in the SardiNIA (N = 3,972) and nine SNPs in the BLSA (N = 1,182) that map within or near the serotonin transporter gene (SLC6A4), and found no association. Along with other large studies that used different phenotypic measures and found no association, this study substantially increases the evidence against a link between 5-HTT variants and Neuroticism-related traits., (2009 Wiley-Liss, Inc.)

Sardinian beta-thalassemia patients all are homozygotes for the same null allele in the beta-globin gene, but the clinical manifestations are extremely variable in severity. Previous studies have shown that the coinheritance of alpha-thalassemia or the presence of genetic variants that sustain fetal hemoglobin production has a strong impact on ameliorating the clinical phenotype. Here we evaluate the contribution of variants in the BCL11A, and HBS1L-MYB genes, implicated in the regulation of fetal hemoglobin, and of alpha-thalassemia coinheritance in 50 thalassemia intermedia and 75 thalassemia major patients. We confirm that alpha-thalassemia and allele C of single nucleotide polymorphism rs-11886868 in BCL11A were selectively represented in thalassemia intermedia patients. Moreover, allele G at single nucleotide polymorphism rs9389268 in the HBS1L-MYB locus was significantly more frequent in the thalassemia intermedia patients. This trio of genetic factors can account for 75% of the variation differences in phenotype severity.

Objective: Personality traits underlie maladaptive behaviors, and cognitive and emotional disturbances that contribute to major preventable causes of global disease burden. This study examines detailed personality profiles of underweight, normal, and overweight individuals to provide insights into the causes and treatments of abnormal weight., Methods: More than half of the population from four towns in Sardinia, Italy (n = 5693; age = 14-94 years; mean +/- standard deviation = 43 +/- 17 years) were assessed on multiple anthropometric measures and 30 facets that comprehensively cover the five major dimensions of personality, using the Revised NEO Personality Inventory., Results: High Neuroticism and low Conscientiousness were associated with being underweight and obese, respectively. High Impulsiveness (specifically eating-behavior items) and low Order were associated with body mass index categories of overweight and obese, and with measures of abdominal adiposity (waist and hip circumference). Those scoring in the top 10% of Impulsiveness were about 4 kg heavier than those in the bottom 10%, an effect independent and larger than the FTO genetic variant. Prospective analyses confirmed that Impulsiveness and Order were significant predictors of general and central measures of adiposity assessed 3 years later., Conclusions: Overweight and obese individuals have difficulty resisting cravings and lack methodical and organized behaviors that might influence diet and weight control. Although individuals' traits have limited impact on the current obesogenic epidemic, personality traits can improve clinical assessment, suggest points of intervention, and help tailor prevention and treatment approaches.

Identifying the genetic variants that regulate fasting glucose concentrations may further our understanding of the pathogenesis of diabetes. We therefore investigated the association of fasting glucose levels with SNPs in 2 genome-wide scans including a total of 5,088 nondiabetic individuals from Finland and Sardinia. We found a significant association between the SNP rs563694 and fasting glucose concentrations (P = 3.5 x 10(-7)). This association was further investigated in an additional 18,436 nondiabetic individuals of mixed European descent from 7 different studies. The combined P value for association in these follow-up samples was 6.9 x 10(-26), and combining results from all studies resulted in an overall P value for association of 6.4 x 10(-33). Across these studies, fasting glucose concentrations increased 0.01-0.16 mM with each copy of the major allele, accounting for approximately 1% of the total variation in fasting glucose. The rs563694 SNP is located between the genes glucose-6-phosphatase catalytic subunit 2 (G6PC2) and ATP-binding cassette, subfamily B (MDR/TAP), member 11 (ABCB11). Our results in combination with data reported in the literature suggest that G6PC2, a glucose-6-phosphatase almost exclusively expressed in pancreatic islet cells, may underlie variation in fasting glucose, though it is possible that ABCB11, which is expressed primarily in liver, may also contribute to such variation.

beta-Thalassemia and sickle cell disease both display a great deal of phenotypic heterogeneity, despite being generally thought of as simple Mendelian diseases. The reasons for this are not well understood, although the level of fetal hemoglobin (HbF) is one well characterized ameliorating factor in both of these conditions. To better understand the genetic basis of this heterogeneity, we carried out genome-wide scans with 362,129 common SNPs on 4,305 Sardinians to look for genetic linkage and association with HbF levels, as well as other red blood cell-related traits. Among major variants affecting HbF levels, SNP rs11886868 in the BCL11A gene was strongly associated with this trait (P < 10(-35)). The C allele frequency was significantly higher in Sardinian individuals with elevated HbF levels, detected by screening for beta-thalassemia, and patients with attenuated forms of beta-thalassemia vs. those with thalassemia major. We also show that the same BCL11A variant is strongly associated with HbF levels in a large cohort of sickle cell patients. These results indicate that BCL11A variants, by modulating HbF levels, act as an important ameliorating factor of the beta-thalassemia phenotype, and it is likely they could help ameliorate other hemoglobin disorders. We expect our findings will help to characterize the molecular mechanisms of fetal globin regulation and could eventually contribute to the development of new therapeutic approaches for beta-thalassemia and sickle cell anemia.

High serum uric acid levels elevate pro-inflammatory-state gout crystal arthropathy and place individuals at high risk for cardiovascular morbidity and mortality. Genome-wide scans in the genetically isolated Sardinian population identified variants associated with serum uric acid levels as a quantitative trait. They mapped within GLUT9, a Chromosome 4 glucose transporter gene predominantly expressed in liver and kidney. SNP rs6855911 showed the strongest association (p = 1.84 x 10(-16)), along with eight others (p = 7.75 x 10(-16) to 6.05 x 10(-11)). Individuals homozygous for the rare allele of rs6855911 (minor allele frequency = 0.26) had 0.6 mg/dl less uric acid than those homozygous for the common allele; the results were replicated in an unrelated cohort from Tuscany. Our results suggest that polymorphisms in GLUT9 could affect glucose metabolism and uric acid synthesis and/or renal reabsorption, influencing serum uric acid levels over a wide range of values., Competing Interests: Competing interests. The authors have declared that no competing interests exist.

Asthma is a multifactorial disease influenced by genetic and environmental factors. In the past decade, several loci and >100 genes have been found to be associated with the disease in at least one population. Among these loci, region 12q13-24 has been implicated in asthma etiology in multiple populations, suggesting that it harbors one or more asthma susceptibility genes. We performed linkage and association analyses by transmission/disequilibrium test and case-control analysis in the candidate region 12q13-24, using the Sardinian founder population, in which limited heterogeneity of pathogenetic alleles for monogenic and complex disorders as well as of environmental conditions should facilitate the study of multifactorial traits. We analyzed our cohort, using a cutoff age of 13 years at asthma onset, and detected significant linkage to a portion of 12q13-24. We identified IRAK-M as the gene contributing to the linkage and showed that it is associated with early-onset persistent asthma. We defined protective and predisposing SNP haplotypes and replicated associations in an outbred Italian population. Sequence analysis in patients found mutations, including inactivating lesions, in the IRAK-M coding region. Immunohistochemistry of lung biopsies showed that IRAK-M is highly expressed in epithelial cells. We report that IRAK-M is involved in the pathogenesis of early-onset persistent asthma. IRAK-M, a negative regulator of the Toll-like receptor/IL-1R pathways, is a master regulator of NF- kappa B and inflammation. Our data suggest a mechanistic link between hyperactivation of the innate immune system and chronic airway inflammation and indicate IRAK-M as a potential target for therapeutic intervention against asthma.

Potential founder population effects on personality trait means and variances were examined in a large, genetically homogeneous sample (N=5,669) from the Ogliastra, an isolated region within Sardinia, Italy. The Italian version of the Revised NEO Personality Inventory showed good psychometric properties: Internal consistency reliabilities ranged from 0.80 to 0.87; the factor structure replicated the American normative structure; and associations with education and gender replicated cross-cultural patterns. The hypothesis that mean trait levels in the Sardinian founder population would differ from mainland Italian values was not supported. Phenotypic variation in this founder population was within the range found in other cultures. However, the hypothesis of restricted phenotypic variation was supported for all five factors and 28 of the 30 facets when a Sardinian subsample matched on age, sex, and education was compared to a mainland Italian sample. The genetic homogeneity effect on the phenotypic expression of complex traits merits further exploration.