Genetic variation in Sirtuin 1 (SIRT1) is associated with lipid profiles but not with longevity in Ashkenazi Jews.
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ABSTRACT:
SUBMITTER: Han J
PROVIDER: S-EPMC4363171 | biostudies-literature | 2015 Apr
REPOSITORIES: biostudies-literature
Publications
Genetic variation in Sirtuin 1 (SIRT1) is associated with lipid profiles but not with longevity in Ashkenazi Jews.
Han Jeehae J Atzmon Gil G Barzilai Nir N Suh Yousin Y
Translational research : the journal of laboratory and clinical medicine 20140922 4
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Project description:Genetic isolates such as the Ashkenazi Jews (AJ) potentially offer advantages in mapping novel loci in whole genome disease association studies. To analyze patterns of genetic variation in AJ, genotypes of 101 healthy individuals were determined using the Affymetrix EAv3 500 K SNP array and compared to 60 CEPH-derived HapMap (CEU) individuals. 435,632 SNPs overlapped and met annotation criteria in the two groups.A small but significant global difference in allele frequencies between AJ and CEU was demonstrated by a mean FST of 0.009 (P < 0.001); large regions that differed were found on chromosomes 2 and 6. Haplotype blocks inferred from pairwise linkage disequilibrium (LD) statistics (Haploview) as well as by expectation-maximization haplotype phase inference (HAP) showed a greater number of haplotype blocks in AJ compared to CEU by Haploview (50,397 vs. 44,169) or by HAP (59,269 vs. 54,457). Average haplotype blocks were smaller in AJ compared to CEU (e.g., 36.8 kb vs. 40.5 kb HAP). Analysis of global patterns of local LD decay for closely-spaced SNPs in CEU demonstrated more LD, while for SNPs further apart, LD was slightly greater in the AJ. A likelihood ratio approach showed that runs of homozygous SNPs were approximately 20% longer in AJ. A principal components analysis was sufficient to completely resolve the CEU from the AJ.LD in the AJ versus was lower than expected by some measures and higher by others. Any putative advantage in whole genome association mapping using the AJ population will be highly dependent on regional LD structure.
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Project description:Patients with Joubert syndrome 2 (JBTS2) suffer from a neurological disease manifested by psychomotor retardation, hypotonia, ataxia, nystagmus, and oculomotor apraxia and variably associated with dysmorphism, as well as retinal and renal involvement. Brain MRI results show cerebellar vermis hypoplasia and additional anomalies of the fourth ventricle, corpus callosum, and occipital cortex. The disease has previously been mapped to the centromeric region of chromosome 11. Using homozygosity mapping in 13 patients from eight Ashkenazi Jewish families, we identified a homozygous mutation, R12L, in the TMEM216 gene, in all affected individuals. Thirty individuals heterozygous for the mutation were detected among 2766 anonymous Ashkenazi Jews, indicating a carrier rate of 1:92. Given the small size of the TMEM216 gene relative to other JBTS genes, its sequence analysis is warranted in all JBTS patients, especially those who suffer from associated anomalies.
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Project description:Contemporary Jews retain a genetic imprint from their Near Eastern ancestry, but obtained substantial genetic components from their neighboring populations during their history. Whether they received any genetic contribution from the Far East remains unknown, but frequent communication with the Chinese has been observed since the Silk Road period. To address this issue, mitochondrial DNA (mtDNA) variation from 55,595 Eurasians are analyzed. The existence of some eastern Eurasian haplotypes in eastern Ashkenazi Jews supports an East Asian genetic contribution, likely from Chinese. Further evidence indicates that this connection can be attributed to a gene flow event that occurred less than 1.4 kilo-years ago (kya), which falls within the time frame of the Silk Road scenario and fits well with historical records and archaeological discoveries. This observed genetic contribution from Chinese to Ashkenazi Jews demonstrates that the historical exchange between Ashkenazim and the Far East was not confined to the cultural sphere but also extended to an exchange of genes.
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Project description:A quantitative genetic analysis of the yeast replicative life span was carried out by sampling the natural genetic variation Genomic DNA was extracted from 39 recombinant lines from a cross between strains S96 and YJM 789.
2012-07-17 | E-GEOD-37590 | biostudies-arrayexpress
Project description:HPC1/RNASEL was recently identified as a candidate gene for hereditary prostate cancer. We identified a novel founder frameshift mutation in RNASEL, 471delAAAG, in Ashkenazi Jews. The mutation frequency in the Ashkenazi population, estimated on the basis of the frequency in 150 healthy young women, was 4% (95% confidence interval [CI] 1.9%-8.4%). Among Ashkenazi Jews, the mutation frequency was higher in patients with prostate cancer (PRCA) than in elderly male control individuals (6.9% vs. 2.4%; odds ratio = 3.0; 95% CI 0.6-15.3; P=.17). 471delAAAG was not detected in the 134 non-Ashkenazi patients with PRCA and control individuals tested. The median age at PRCA diagnosis did not differ significantly between the Ashkenazi carriers and noncarriers included in our study. However, carriers received diagnoses at a significantly earlier age, compared with patients with PRCA who were registered in the Israeli National Cancer Registry (65 vs. 74.4 years, respectively; P<.001). When we examined two brothers with PRCA, we found a heterozygous 471delAAAG mutation in one and a homozygous mutation in the other. Loss of heterozygosity was demonstrated in the tumor of the heterozygous sib. Taken together, these data suggest that the 471delAAAG null mutation is associated with PRCA in Ashkenazi men. However, additional studies are required to determine whether this mutation confers increased risk for PRCA in this population.
| S-EPMC378554 | biostudies-literature
Project description:BackgroundVariants in GBA are the most common genetic risk factor for Parkinson's disease (PD), and are especially prevalent in the Ashkenazi Jewish (AJ) population. However, most studies on GBA in AJ genotype only seven selected Gaucher-associated pathogenic variants rather than sequencing the whole gene, which may leave carriers of PD-associated GBA variants undiscovered.MethodsGBA was fully sequenced using molecular inversion probes (MIPs) and Sanger sequencing in 735 AJ PD patients and 662 AJ controls, from Israel and New York. Additional AJ control data (n = 3044) from the Inflammatory Bowel Disease Exome Portal was used.ResultsFull GBA sequencing increased the number of variants discovered by 17.4%, compared to targeted genotyping. An additional 17 PD patients were identified with GBA-associated PD. The p.E326K variant was found in 1.6% of AJ PD patients, making it the second most common PD-associated GBA variant in AJ. GBA variants were found in 18% of PD patients and 7.5% of controls (OR = 2.7, 95%CI = 1.9-3.8, p < 0.0001).ConclusionWithout full sequencing of GBA, or at minimum including p.E326K in the genotyping panel, a significant proportion of variant carriers go undiscovered and may be incorrectly assigned as non-carriers in studies or clinical trials.
| S-EPMC6261782 | biostudies-literature
Project description:The phenotype of Parkinson's disease (PD) in patients with and without leucine-rich repeat kinase 2 (LRRK2) G2019S mutations reportedly is similar; however, large, uniformly evaluated series are lacking. The objective of this study was to characterize the clinical phenotype of Ashkenazi Jewish (AJ) PD carriers of the LRRK2 G2019S mutation. We studied 553 AJ PD patients, including 65 patients who were previously reported, from three sites (two in New York and one in Tel-Aviv). Glucocerebrosidase (GBA) mutation carriers were excluded. Evaluations included the Montreal Cognitive Assessment (MoCA), the Unified Parkinson's Disease Rating Scale (UPDRS), the Geriatric Depression Scale (GDS) and the Non-Motor Symptoms (NMS) questionnaire. Regression models were constructed to test the association between clinical and demographic features and LRRK2 status (outcome) in 488 newly recruited participants. LRRK2 G2019S carriers (n?=?97) and non-carriers (n?=?391) were similar in age and age at onset of PD. Carriers had longer disease duration (8.6 years vs. 6.1 years; P?<?0.001), were more likely to be women (51.5% vs. 37.9%; P?=?0.015), and more often reported first symptoms in the lower extremities (40.0% vs. 19.2%; P?<?0.001). In logistic models that were adjusted for age, disease duration, sex, education, and site, carriers were more likely to have lower extremity onset (P?<?0.001), postural instability and gait difficulty (PIGD) (P?=?0.043), and a persistent levodopa response for >5 years (P?=?0.042). Performance on the UPDRS, MoCA, GDS, and NMS did not differ by mutation status. PD in AJ LRRK2 G2019S mutation carriers is similar to idiopathic PD but is characterized by more frequent lower extremity involvement at onset and PIGD without the associated cognitive impairment.
| S-EPMC3859844 | biostudies-literature
Project description:In a recent interdisciplinary study, Das et al. have attempted to trace the homeland of Ashkenazi Jews and of their historical language, Yiddish (Das et al. 2016 Localizing Ashkenazic Jews to Primeval Villages in the Ancient Iranian Lands of Ashkenaz. Genome Biol Evol. 8:1132-1149). Das et al. applied the geographic population structure (GPS) method to autosomal genotyping data and inferred geographic coordinates of populations supposedly ancestral to Ashkenazi Jews, placing them in Eastern Turkey. They argued that this unexpected genetic result goes against the widely accepted notion of Ashkenazi origin in the Levant, and speculated that Yiddish was originally a Slavic language strongly influenced by Iranian and Turkic languages, and later remodeled completely under Germanic influence. In our view, there are major conceptual problems with both the genetic and linguistic parts of the work. We argue that GPS is a provenancing tool suited to inferring the geographic region where a modern and recently unadmixed genome is most likely to arise, but is hardly suitable for admixed populations and for tracing ancestry up to 1,000 years before present, as its authors have previously claimed. Moreover, all methods of historical linguistics concur that Yiddish is a Germanic language, with no reliable evidence for Slavic, Iranian, or Turkic substrata.
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Project description:A quantitative genetic analysis of the yeast replicative life span was carried out by sampling the natural genetic variation
2012-07-18 | GSE37590 | GEO
Project description:BackgroundColorectal neoplasia is one of the most common tumors affecting Western populations.MethodsIn this study we used a custom amplicon sequencing platform and an in-house bioinformatic pipeline to study constitutional DNA from two different case series of Ashkenazi Jews undergoing colonoscopy (n = 765). The first series all had pathologically confirmed colorectal adenomas and/or carcinoma. The second series consisted of persons who had undergone a colonoscopy within the five years prior to ascertainment, regardless of findings. Ninety-one percent of all patients were asymptomatic at the time of colonoscopy.ResultsIn the first group (n = 438), we identified 65 founder variants (56 in APC, 2 in GREM1, 3 in MSH2 and 4 in BLM). In the second group (n = 327), the findings were 30, nothing, 1 and 1, respectively, as well as 2 MSH6 variants.ConclusionsOverall, we found that 10 to 15% of Ashkenazi Jewish persons undergoing colonoscopy harbor variants of interest in colorectal and/or polyposis predisposition. This includes pathogenic variants in MSH6, which is associated with colorectal cancer but not with polyposis. We identified no pathogenic variants in more recently discovered polyposis predisposition genes (POLE, POLD1 or NTHL1), rendering the presence of such founder variants rare.
| S-EPMC11523938 | biostudies-literature