Genetic analysis revealed a gene variant in the Sardinian population that was associated with autoimmune disease. In the variant gene, a deletion yielded a shorter transcript that escaped inhibition ...by microRNA, leading to overexpression of BAFF.
Multiple sclerosis and systemic lupus erythematosus (SLE) are autoimmune diseases caused by largely unknown environmental factors acting in genetically susceptible persons. Genomewide association studies have provided statistical support for more than 110 independent signals for multiple sclerosis and 43 for SLE.
1
–
3
Although several signals are near genes involved in immunologic processes, the effector mechanisms for most associations remain unknown.
A useful approach to explore disease mechanisms is to search for genetic variants that affect both the risk of autoimmune disease and quantitative immune variables such as circulating levels of immune-cell populations, immunoglobulins, and cytokines.
4
,
5
This approach can reveal . . .
The obesity epidemic is responsible for a substantial economic burden in developed countries and is a major risk factor for type 2 diabetes and cardiovascular disease. The disease is the result not ...only of several environmental risk factors, but also of genetic predisposition. To take advantage of recent advances in gene-mapping technology, we executed a genome-wide association scan to identify genetic variants associated with obesity-related quantitative traits in the genetically isolated population of Sardinia. Initial analysis suggested that several SNPs in the FTO and PFKP genes were associated with increased BMI, hip circumference, and weight. Within the FTO gene, rs9930506 showed the strongest association with BMI (p = 8.6 x10(-7)), hip circumference (p = 3.4 x 10(-8)), and weight (p = 9.1 x 10(-7)). In Sardinia, homozygotes for the rare "G" allele of this SNP (minor allele frequency = 0.46) were 1.3 BMI units heavier than homozygotes for the common "A" allele. Within the PFKP gene, rs6602024 showed very strong association with BMI (p = 4.9 x 10(-6)). Homozygotes for the rare "A" allele of this SNP (minor allele frequency = 0.12) were 1.8 BMI units heavier than homozygotes for the common "G" allele. To replicate our findings, we genotyped these two SNPs in the GenNet study. In European Americans (N = 1,496) and in Hispanic Americans (N = 839), we replicated significant association between rs9930506 in the FTO gene and BMI (p-value for meta-analysis of European American and Hispanic American follow-up samples, p = 0.001), weight (p = 0.001), and hip circumference (p = 0.0005). We did not replicate association between rs6602024 and obesity-related traits in the GenNet sample, although we found that in European Americans, Hispanic Americans, and African Americans, homozygotes for the rare "A" allele were, on average, 1.0-3.0 BMI units heavier than homozygotes for the more common "G" allele. In summary, we have completed a whole genome-association scan for three obesity-related quantitative traits and report that common genetic variants in the FTO gene are associated with substantial changes in BMI, hip circumference, and body weight. These changes could have a significant impact on the risk of obesity-related morbidity in the general population.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
β-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 β-thalassemia, and patients with attenuated forms of β-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 β-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 β-thalassemia and sickle cell anemia.
The B vitamins are components of one-carbon metabolism (OCM) that contribute to DNA synthesis and methylation. Homocysteine, a by-product of OCM, has been associated with coronary heart disease, ...stroke and neurological disease. To investigate genetic factors that affect circulating vitamin B6, vitamin B12, folate and homocysteine, a genome-wide association analysis was conducted in the InCHIANTI (N = 1175), SardiNIA (N = 1115), and BLSA (N = 640) studies. The top loci were replicated in an independent sample of 687 participants in the Progetto Nutrizione study. Polymorphisms in the
ALPL gene (rs4654748, p = 8.30 × 10
−18) were associated with vitamin B6 and
FUT2 (rs6022662, p = 2.83 × 10
−20) with vitamin B12 serum levels. The association of
MTHFR, a gene consistently associated with homocysteine, was confirmed in this meta-analysis. The
ALPL gene likely influences the catabolism of vitamin B6 while
FUT2 interferes with absorption of vitamin B12. These findings highlight mechanisms that affect vitamin B6, vitamin B12 and homocysteine serum levels.
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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
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.
We report on the influence of ~22 million variants on 731 immune cell traits in a cohort of 3,757 Sardinians. We detected 122 significant (P < 1.28 × 10
) independent association signals for 459 cell ...traits at 70 loci (53 of them novel) identifying several molecules and mechanisms involved in cell regulation. Furthermore, 53 signals at 36 loci overlapped with previously reported disease-associated signals, predominantly for autoimmune disorders, highlighting intermediate phenotypes in pathogenesis. Collectively, our findings illustrate complex genetic regulation of immune cells with highly selective effects on autoimmune disease risk at the cell-subtype level. These results identify drug-targetable pathways informing the design of more specific treatments for autoimmune diseases.
We report ∼17.6 million genetic variants from whole-genome sequencing of 2,120 Sardinians; 22% are absent from previous sequencing-based compilations and are enriched for predicted functional ...consequences. Furthermore, ∼76,000 variants common in our sample (frequency >5%) are rare elsewhere (<0.5% in the 1000 Genomes Project). We assessed the impact of these variants on circulating lipid levels and five inflammatory biomarkers. We observe 14 signals, including 2 major new loci, for lipid levels and 19 signals, including 2 new loci, for inflammatory markers. The new associations would have been missed in analyses based on 1000 Genomes Project data, underlining the advantages of large-scale sequencing in this founder population.
The complex network of specialized cells and molecules in the immune system has evolved to defend against pathogens, but inadvertent immune system attacks on “self” result in autoimmune disease. Both ...genetic regulation of immune cell levels and their relationships with autoimmunity are largely undetermined. Here, we report genetic contributions to quantitative levels of 95 cell types encompassing 272 immune traits, in a cohort of 1,629 individuals from four clustered Sardinian villages. We first estimated trait heritability, showing that it can be substantial, accounting for up to 87% of the variance (mean 41%). Next, by assessing ∼8.2 million variants that we identified and confirmed in an extended set of 2,870 individuals, 23 independent variants at 13 loci associated with at least one trait. Notably, variants at three loci (HLA, IL2RA, and SH2B3/ATXN2) overlap with known autoimmune disease associations. These results connect specific cellular phenotypes to specific genetic variants, helping to explicate their involvement in disease.
Display omitted
•Immune system analysis of 95 distinct cell types using flow cytometry and GWAS•An unexpectedly large genetic component drives variation in immune cell numbers•Sequencing-based GWAS reveals new immune cell trait-associated SNPs•Immune trait-disease overlapping associations point to specific cells as risk factors
To analyze the role of genetics in immunity regulation and immune cell numbers, a combination of flow cytometry and GWA analyses profiles 95 cell types of the innate and adaptive immune system to connect specific cellular phenotypes to immune-related diseases predisposition.
Genetic variation within the male-specific portion of the Y chromosome (MSY) can clarify the origins of contemporary populations, but previous studies were hampered by partial genetic information. ...Population sequencing of 1204 Sardinian males identified 11,763 MSY single-nucleotide polymorphisms, 6751 of which have not previously been observed. We constructed a MSY phylogenetic tree containing all main haplogroups found in Europe, along with many Sardinian-specific lineage clusters within each haplogroup. The tree was calibrated with archaeological data from the initial expansion of the Sardinian population ∼7700 years ago. The ages of nodes highlight different genetic strata in Sardinia and reveal the presumptive timing of coalescence with other human populations. We calculate a putative age for coalescence of ∼180,000 to 200,000 years ago, which is consistent with previous mitochondrial DNA—based estimates.
PDF
