Identification of population substructure among Jews using STR markers and dependence on reference populations included

Background: Detecting population substructure is a critical issue for association studies of health behaviors and other traits. Whether inherent in the population or an artifact of marker choice, determining aspects of a population's genetic history as potential sources of substructure can aid in design of future genetic studies. Jewish populations, among which association studies are often conducted, have a known history of migrations. As a necessary step in understanding population structure to conduct valid association studies of health behaviors among Israeli Jews, we investigated genetic signatures of this history and quantified substructure to facilitate future investigations of these phenotypes in this population. Results: Using 32 autosomal STR markers and the program STRUCTURE, we differentiated between Ashkenazi (AJ, N = 135) and non-Ashkenazi (NAJ, N = 226) Jewish populations in the form of Northern and Southern geographic genetic components (AJ north 73%, south 23%, NAJ north 33%, south 60%). The ability to detect substructure within these closely related populations using a small STR panel was contingent on including additional samples representing major continental populations in the analyses. Conclusions: Although clustering programs such as STRUCTURE are designed to assign proportions of ancestry to individuals without reference population information, when Jewish samples were analyzed in the absence of proxy parental populations, substructure within Jews was not detected. Generally, for samples with a given grandparental country of birth, STRUCTURE assignment values to Northern, Southern, African and Asian clusters agreed with mitochondrial DNA and Y-chromosomal data from previous studies as well as historical records of migration and intermarriage

Demographic changes and marker properties affect detection of human population differentiation

<p>Abstract</p> <p>Background</p> <p>Differentiating genetically between populations is valuable for admixture and population stratification detection and in understanding population history. This is easy to achieve for major continental populations, but not for closely related populations. It has been claimed that a large marker panel is necessary to reliably distinguish populations within a continent. We investigated whether empirical genetic differentiation could be accomplished efficiently among three Asian populations (Hmong, Thai, and Chinese) using a small set of highly variable markers (15 tetranucleotide and 17 dinucleotide repeats).</p> <p>Results</p> <p>Hmong could be differentiated from Thai and Chinese based on multi-locus genotypes, but Thai and Chinese were indistinguishable from each other. We found significant evidence for a recent population bottleneck followed by expansion in the Hmong that was not present in the Thai or Chinese. Tetranucleotide repeats were less useful than dinucleotide repeat markers in distinguishing between major continental populations (Asian, European, and African) while both successfully distinguished Hmong from Thai and Chinese.</p> <p>Conclusion</p> <p>Demographic history contributes significantly to robust detection of intracontinental population structure. Populations having experienced a rapid size reduction may be reliably distinguished as a result of a genetic drift -driven redistribution of population allele frequencies. Tetranucleotide markers, which differ from dinucleotide markers in mutation mechanism and rate, are similar in information content to dinucleotide markers in this situation. These factors should be considered when identifying populations suitable for gene mapping studies and when interpreting interpopulation relationships based on microsatellite markers.</p

Sequence variation and linkage disequilibrium in the GABA transporter-1 gene (SLC6A1) in five populations: implications for pharmacogenetic research

<p>Abstract</p> <p>Background</p> <p>GABA transporter-1 (GAT-1; genetic locus <it>SLC6A1</it>) is emerging as a novel target for treatment of neuropsychiatric disorders. To understand how population differences might influence strategies for pharmacogenetic studies, we identified patterns of genetic variation and linkage disequilibrium (LD) in <it>SLC6A1 </it>in five populations representing three continental groups.</p> <p>Results</p> <p>We resequenced 12.4 kb of <it>SLC6A1</it>, including the promoters, exons and flanking intronic regions in African-American, Thai, Hmong, Finnish, and European-American subjects (total n = 40). LD in <it>SLC6A1 </it>was examined by genotyping 16 SNPs in larger samples. Sixty-three variants were identified through resequencing. Common population-specific variants were found in African-Americans, including a novel 21-bp promoter region variable number tandem repeat (VNTR), but no such variants were found in any of the other populations studied. Low levels of LD and the absence of major LD blocks were characteristic of all five populations. African-Americans had the highest genetic diversity. European-Americans and Finns did not differ in genetic diversity or LD patterns. Although the Hmong had the highest level of LD, our results suggest that a strategy based on the use of tag SNPs would not translate to a major improvement in genotyping efficiency.</p> <p>Conclusion</p> <p>Owing to the low level of LD and presence of recombination hotspots, <it>SLC6A1 </it>may be an example of a problematic gene for association and haplotype tagging-based genetic studies. The 21-bp promoter region VNTR polymorphism is a putatively functional candidate allele for studies focusing on variation in GAT-1 function in the African-American population.</p

T cell activation and deficits in T regulatory cells are associated with major depressive disorder and severity of depression

Abstract Major depressive disorder (MDD) is associated with T cell activation, but no studies have examined the combined effects of T cell activation and deficits in T regulatory (Treg) cells on the severity of acute phase MDD. Using flow cytometry, we determined the percentage and median fluorescence intensity of CD69, CD71, CD40L, and HLADR-bearing CD3+, CD4+, and CD8+ cells, and cannabinoid type 1 receptor (CB1), CD152 and GARP (glycoprotein A repetitions predominant)-bearing CD25+ FoxP3 T regulatory (Treg) cells in 30 MDD patients and 20 healthy controls in unstimulated and stimulated (anti-CD3/CD28) conditions. Based on cytokine levels, we assessed M1 macrophage, T helper (Th)-1 cell, immune-inflammatory response system (IRS), T cell growth, and neurotoxicity immune profiles. We found that the immune profiles (including IRS and neurotoxicity) were significantly predicted by decreased numbers of CD152 or GARP-bearing CD25+ FoxP3 cells or CD152 and GARP expression in combination with increases in activated T cells (especially CD8+ CD40L+ percentage and expression). MDD patients showed significantly increased numbers of CD3+ CD71+, CD3+ CD40L+, CD4+ CD71+, CD4+ CD40L+, CD4+ HLADR+, and CD8+ HLADR+ T cells, increased CD3+ CD71+, CD4+ CD71+ and CD4+ HLADR+ expression, and lowered CD25+ FoxP3 expression and CD25+ FoxP+ CB1+ numbers as compared with controls. The Hamilton Depression Rating Scale score was strongly predicted (between 30 and 40% of its variance) by a lower number of CB1 or GARP-bearing Treg cells and one or more activated T cell subtypes (especially CD8+ CD40L+). In conclusion, increased T helper and cytotoxic cell activation along with decreased Treg homeostatic defenses are important parts of MDD that lead to enhanced immune responses and, as a result, neuroimmunotoxicity

The Immune Profile of Major Dysmood Disorder: Proof of Concept and Mechanism Using the Precision Nomothetic Psychiatry Approach

Major depressive disorder and a major depressive episode (MDD/MDE) are characterized by activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS). In MDD/MDE, recent precision nomothetic psychiatry studies discovered a new endophenotype class, namely major dysmood disorder (MDMD), a new pathway phenotype, namely reoccurrence of illness (ROI), and a new model of the phenome of depression. The aim of the present study is to examine the association between ROI, the phenome of depression, and MDMD’s features and IRS, CIRS, macrophages (M1), T helper (Th)1, Th2, Th17, T regulatory, and growth factor (GF) profiles. Culture supernatants of unstimulated and stimulated (5 μg/mL of PHA and 25 μg/mL of LPS) diluted whole blood of 30 MDD/MDE patients and 20 controls were assayed for cytokines/GF using the LUMINEX assay. MDMD was characterized by increased M1, Th1, Th2, Th17, Treg, IRS, CIRS, neurotoxicity, and GF profiles. Factor analysis shows that ROI features and immune-GF profiles may be combined into a new pathway phenotype (an extracted latent vector). ROI, lifetime and recent suicidal behaviors, and severity of depression are significantly associated with immunotoxicity and GF profiles. Around 80.0% of the variance in the phenome is predicted by ROI and neurotoxicity or the IRS/CIRS ratio. The molecular pathways underpinning ROI-associated sensitization of immune/growth networks are transmembrane receptor protein kinase-triggered STAT protein phosphorylation, TLR/NF-κB, JAK-STAT, and the main proliferation/survival PI3K/Akt/RAS/MAPK pathway. In conclusion, MDMD’s heightened immune responses are the consequence of ROI-associated sensitization combined with immunostimulatory triggers

In Vitro Effects of Cannabidiol on Activated Immune&ndash;Inflammatory Pathways in Major Depressive Patients and Healthy Controls

Major depressive disorder and major depressive episodes (MDD/MDE) are characterized by the activation of the immune&ndash;inflammatory response system (IRS) and the compensatory immune&ndash;regulatory system (CIRS). Cannabidiol (CBD) is a phytocannabinoid isolated from the cannabis plant, which is reported to have antidepressant-like and anti-inflammatory effects. The aim of the present study is to examine the effects of CBD on IRS, CIRS, M1, T helper (Th)-1, Th-2, Th-17, T regulatory (Treg) profiles, and growth factors in depression and healthy controls. Culture supernatant of stimulated (5 &mu;g/mL of PHA and 25 &mu;g/mL of LPS) whole blood of 30 depressed patients and 20 controls was assayed for cytokines using the LUMINEX assay. The effects of three CBD concentrations (0.1 &micro;g/mL, 1 &micro;g/mL, and 10 &micro;g/mL) were examined. Depression was characterized by significantly increased PHA + LPS-stimulated Th-1, Th-2, Th-17, Treg, IRS, CIRS, and neurotoxicity profiles. CBD 0.1 &micro;g/mL did not have any immune effects. CBD 1.0 &micro;g/mL decreased CIRS activities but increased growth factor production, while CBD 10.0 &micro;g/mL suppressed Th-1, Th-17, IRS, CIRS, and a neurotoxicity profile and enhanced T cell growth and growth factor production. CBD 1.0 to 10.0 &micro;g/mL dose-dependently decreased sIL-1RA, IL-8, IL-9, IL-10, IL-13, CCL11, G-CSF, IFN-&gamma;, CCL2, CCL4, and CCL5, and increased IL-1&beta;, IL-4, IL-15, IL-17, GM-CSF, TNF-&alpha;, FGF, and VEGF. In summary, in this experiment, there was no beneficial effect of CBD on the activated immune profile of depression and higher CBD concentrations can worsen inflammatory processes

The Immune Profile of Major Dysmood Disorder: Proof of Concept and Mechanism Using the Precision Nomothetic Psychiatry Approach

Major depressive disorder and a major depressive episode (MDD/MDE) are characterized by activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS). In MDD/MDE, recent precision nomothetic psychiatry studies discovered a new endophenotype class, namely major dysmood disorder (MDMD), a new pathway phenotype, namely reoccurrence of illness (ROI), and a new model of the phenome of depression. The aim of the present study is to examine the association between ROI, the phenome of depression, and MDMD&rsquo;s features and IRS, CIRS, macrophages (M1), T helper (Th)1, Th2, Th17, T regulatory, and growth factor (GF) profiles. Culture supernatants of unstimulated and stimulated (5 &mu;g/mL of PHA and 25 &mu;g/mL of LPS) diluted whole blood of 30 MDD/MDE patients and 20 controls were assayed for cytokines/GF using the LUMINEX assay. MDMD was characterized by increased M1, Th1, Th2, Th17, Treg, IRS, CIRS, neurotoxicity, and GF profiles. Factor analysis shows that ROI features and immune-GF profiles may be combined into a new pathway phenotype (an extracted latent vector). ROI, lifetime and recent suicidal behaviors, and severity of depression are significantly associated with immunotoxicity and GF profiles. Around 80.0% of the variance in the phenome is predicted by ROI and neurotoxicity or the IRS/CIRS ratio. The molecular pathways underpinning ROI-associated sensitization of immune/growth networks are transmembrane receptor protein kinase-triggered STAT protein phosphorylation, TLR/NF-&kappa;B, JAK-STAT, and the main proliferation/survival PI3K/Akt/RAS/MAPK pathway. In conclusion, MDMD&rsquo;s heightened immune responses are the consequence of ROI-associated sensitization combined with immunostimulatory triggers

Adverse Childhood Experiences Predict the Phenome of Affective Disorders and These Effects Are Mediated by Staging, Neuroimmunotoxic and Growth Factor Profiles

Adverse childhood experiences (ACEs) enhance pro-inflammatory and pro-oxidant responses. In affective disorders, recent precision nomothetic psychiatry studies disclosed new pathway phenotypes, including an ROI—reoccurrence of illness (ROI)—oxidative stress latent construct. The aim of the present study is to delineate a) whether ACEs sensitize the M1 macrophage, the T helper cells (Th)1, Th2, and Th17, the IRS (immune-inflammatory-responses system), the CIRS (compensatory immunoregulatory system), and the neuroimmunotoxic and growth factor (GF) profiles and whether they are associated with ROI and the phenome of affective disorders and b) the molecular pathways underpinning the effects of the ACEs. We collected supernatants of stimulated (5 μg/mL of PHA and 25 μg/mL of LPS) and unstimulated diluted whole blood in 20 healthy controls and 30 depressed patients and measured a panel of 27 cytokines/GF using a Luminex method. ACEs (comprising mental and physical trauma, mental neglect, domestic violence, family history of mental disease, and parent loss) are accompanied by the increased stimulated, but not unstimulated, production of M1, Th1, Th2, Th17, IRS, neuroimmunotoxic, and GF profiles and are strongly correlated with ROI and the phenome. A latent vector extracted from the ROI features (recurrent episodes and suicidal behaviors) and the IRS/neuroimmunotoxic/GF profiles explains 66.8% of the variance in the phenome and completely mediates the effects of ACEs on the phenome. Enrichment analysis showed that the ACE-associated sensitization of immune/GF profiles involves JAK-STAT, nuclear factor-κB, tumor necrosis factor-α, G-protein coupled receptor, PI3K/Akt/RAS/MAPK, and hypoxia signaling. In summary, the ACE-induced sensitization of immune pathways and secondary immune hits predicts the phenome of affective disorders