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INTRODUCTION: Most of previous studies have examined effects of acute psychological stress in humans on selected panels of genes. The genomic approach may help identify novel genes that underline biological mechanisms of acute psychological stress responses. OBJECTIVE: This exploratory study aimed to investigate genome-wide transcriptional activity changes in response to acute psychological stress. METHODS: The sample included 40 healthy women (mean age 31±11.6 years). Twenty-two participants had a stress experience induced by the Trier Social Stress Test (TSST) (experimental group) and 18 did not (control group). Psychological stress levels and hemodynamic changes were assessed before and after the TSST. The peripheral blood samples obtained before and after the TSST were processed for mRNA-sequencing. RESULTS: The psychological and hemodynamic stress parameters indicated that the TSST induced moderate levels of stress in the experimental group. Six genes (HCG26, HCP5, HLA-F, HLA-F-AS1, LOC1019287, and SLC22A16) were up-regulated, and five genes (CA1, FBXO9, SNCA, STRADB, and TRMT12) were down-regulated, among those who experienced the stress induction, compared with the control group. Nine genes out of 11 were found in the network of endocrine system disorders, neurological disease, and organismal injury and abnormalities. CONCLUSION: The identified genes such as HCP5, SLC22A16, and SNCA have previously been proposed as the therapeutic targets of cancer and Parkinson’s disease. Future studies are suggested to examine pathological mechanisms by which the identified genes may mediate the association between psychological stress and adverse health outcomes. Such studies may ultimately identify therapeutic targets that enhance biological resilience to the adverse effects of psychological stress.

ObjectiveGenetic risk scores (GRS) have been developed that differentiate individuals with type 1 diabetes from those with other forms of diabetes and are starting to be used for population screening; however, most studies were conducted in European-ancestry populations. This study identifies novel genetic variants associated with type 1 diabetes risk in African-ancestry participants and develops an African-specific GRS.Research design and methodsWe generated single nucleotide polymorphism (SNP) data with the ImmunoChip on 1,021 African-ancestry participants with type 1 diabetes and 2,928 control participants. HLA class I and class II alleles were imputed using SNP2HLA. Logistic regression models were used to identify genome-wide significant (P < 5.0 × 10-8) SNPs associated with type 1 diabetes in the African-ancestry samples and validate SNPs associated with risk in known European-ancestry loci (P < 2.79 × 10-5).ResultsAfrican-specific (HLA-DQA1*03:01-HLA-DQB1*02:01) and known European-ancestry HLA haplotypes (HLA-DRB1*03:01-HLA-DQA1*05:01-HLA-DQB1*02:01, HLA-DRB1*04:01-HLA-DQA1*03:01-HLA-DQB1*03:02) were significantly associated with type 1 diabetes risk. Among European-ancestry defined non-HLA risk loci, six risk loci were significantly associated with type 1 diabetes in subjects of African ancestry. An African-specific GRS provided strong prediction of type 1 diabetes risk (area under the curve 0.871), performing significantly better than a European-based GRS and two polygenic risk scores in independent discovery and validation cohorts.ConclusionsGenetic risk of type 1 diabetes includes ancestry-specific, disease-associated variants. The GRS developed here provides improved prediction of type 1 diabetes in African-ancestry subjects and a means to identify groups of individuals who would benefit from immune monitoring for early detection of islet autoimmunity.

Haplotype for glucose QTL Bglu17 on chromosome 9. Analysis was performed in the same way as for Hdlq17 illustrated above. (PDF 82 kb)

Haplotype analysis to prioritize candidate genes for HDL QTL Hdlq17 on chromosome 9. Sanger SNP database ( http://www.sanger.ac.uk/sanger/Mouse_SnpViewer/rel-1410 ) was used to prioritize candidate genes for this locus, which were mapped in 3 separate crosses derived from different inbred strains. A high allele strain is the one that displays a larger allelic effect on HDL level at the locus and a low allele strain is the one showing a smaller allelic effect on HDL at the locus. (PDF 86 kb)

Haplotype for glucose QTL Bglu17 on chromosome 9. Analysis was performed in the same way as for Hdlq17 illustrated above. (PDF 82 kb)

Online Data Supplement for â Genome-wide association study of subclinical interstitial lung disease in MESAâ . (DOCX 14799 kb)

Hutchinson-Gilford progeria syndrome (HGPS) is a rare precocious aging syndrome caused by mutations in LMNA that lead to synthesis of a mutant form of prelamin A, generally called progerin, that cannot be processed to mature lamin A. Most HGPS patients have a recurrent heterozygous de novo mutation in exon 11 of LMNA, c.1824C>T/p.G608G; this synonymous mutation activates a nearby cryptic splice donor site, resulting in synthesis of the mutant prelamin A, progerin, which lacks 50 amino acids within the carboxyl-terminal domain. Abnormal splicing is incomplete, so the mutant allele produces some normally-spliced transcripts. Nevertheless, the synthesis of progerin is sufficient to cause misshapen nuclei in cultured cells and severe disease phenotypes in affected patients. Here we present two patients with extraordinarily severe forms of progeria caused by unusual mutations in LMNA. One had a splice site mutation (c.1968+1G>A; or IVS11+1G>A), and the other had a novel synonymous coding region mutation (c.1821G>A/p.V607V). Both mutations caused very frequent use of the same exon 11 splice donor site that is activated in typical HGPS patients. As a consequence, the ratios of progerin mRNA and protein to wild-type were higher than in typical HGPS patients. Fibroblasts from both patients exhibited nuclear shape abnormalities typical of HGPS, and cells treated with a protein farnesyltransferase inhibitor exhibited fewer misshapen nuclei. Thus, farnesyltransferase inhibitors may prove to be useful even when progerin expression levels are higher than those in typical HGPS patients.