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PubMed1979

[Problems in the genetics of stress. IV. A genetic analysis of the level of autonomic reactivity in emotional stress in rats].

A genetic analysis of hypertensive reactions under condition of emotional stress in three inbred strains of rats (Wistar, Sprague-Dowly and August) and their F1 reciprocal hybrids is carried out. Highly significant genotypic differences in the arterial pressure level during emotional stress and no genetic diversity in the basal state were found. Application of our own methos to genetic analysis of incomplete diallelic tables for Griffing's experimental design 1 (model 1) showed an existence of significant additive component of genetic variance in autonomic reactivity under the stress. The role of the stress as a factor of differentiation of the genetic structure of population is discussed.

Analysis of Variance↗

PubMed2025

Multivariate genetic of 2.2 million individuals demonstrate genetic influences on substance use disorders operate via behavioral disinhibition and substance-specific risk.

Ongoing efforts to identify genes involved in substance use disorders (SUDs) often focus on individual disorders despite high rates of co-occurrence with each other and other externalizing traits. Here, we investigate whether incorporating data on other externalizing traits can boost power to detect without sacrificing specificity of SUD genetic signal. We used multivariate genomic analyses and downstream biological annotation and genetic association analyses to explore this question. We found that joint analysis of SUDs and other externalizing traits resulted in increased insights into the neurobiology of broad and substance-specific SUD risk. We found no evidence of loss of specificity for SUD genetic signal but note improvements in our ability to characterize the neurobiology of broad and substance-specific SUD genetic effects. Our findings suggest that genetic risk for SUDs operates largely via pathways shared with other behaviors characterized by behavioral disinhibition, with additional substance-specific risk, and that modeling this shared disposition improves gene discovery.

Journal Article↗

PubMed2025

Genetic analysis in African ancestry populations reveals genetic contributors to lung cancer susceptibility.

Striking disparities in lung cancer exist, with Black/African American individuals disproportionately affected by lung cancer, yet the genetic architecture in African ancestry individuals is poorly understood. We aimed to address this by performing a comprehensive genetic association study of lung cancer, incorporating local ancestry, across 6,490 African ancestry individuals (2,390 individuals with lung cancer and 4,100 control subjects). We identified a single genome-wide significant (p < 5 × 10-8) locus, 15q25.1 (lead SNP rs17486278, OR [95% CI] = 1.34 [1.23-1.45], p = 4.52 × 10-12), that has consistently shown a strong association with lung cancer across populations. Additionally, we identified nine suggestive (p < 1 × 10-6) loci. Four of these loci (3p12.1, 8q22.2, 14q11.2, and 18q22.3) have no prior reported associations with lung cancer. We performed a multi-ancestry lung cancer meta-analysis using prior large-scale summary statistics from European and Asian ancestry populations, incorporating our African ancestry results. The meta-analysis identified 17 genome-wide significant loci, including an association with locus 4q35.2 (p = 1.22 × 10-8), a genomic region that has been previously linked to forced expiratory volume. Genome-wide SNP-based heritability for lung cancer was 16% among African ancestry individuals. Follow-up in silico functional analyses identified genetically regulated gene expression (GReX) of nine genes (AC012184.3, ADK, CCDC12, CHRNA3, EML4, PSMA4, SNRNP200, TMEM50A, and ZYG11A) associated with lung cancer risk and biological pathways relevant to cancer and lung function. Cumulatively, these findings further elucidate the genetic architecture of lung cancer in African ancestry individuals, confirming prior loci and revealing new loci.

Female↗

PubMed2026

Mapping the immune-genetic architecture of Epstein-Barr virus-related phenotypes and multiple sclerosis through a single-cell genetic framework for target prioritization and pharmacologic hypothesis generation.

BACKGROUND: Multiple sclerosis (MS) is a severe neuroinflammatory disease causing substantial long-term disability. Strong epidemiologic evidence links Epstein-Barr virus (EBV) exposure with MS risk, but genetic evidence for immune target prioritization in EBV-related phenotypes remains limited. METHODS: We integrated single-cell cis-eQTL data from 14 immune cell types with GWASs of an EBV-related clinical phenotype and MS using a single-cell Mendelian randomization framework with colocalization analyses. Candidate eGenes were evaluated in independent cohorts. For multi-SNP instruments, we performed heterogeneity, pleiotropy, MR-Egger, weighted median, mode-based, and MR-PRESSO sensitivity analyses. We also conducted phenome-wide association analyses and queried DrugBank to annotate candidate compounds targeting prioritized genes. RESULTS: We prioritized 43 immune-cell-specific candidate eGenes with convergent genetic support, including 6 for the EBV-related phenotype and 37 for MS. SERPINB1 in NK cells was associated with increased risk of the EBV-related phenotype, whereas HLA-G was associated with decreased risk. For MS, APOM and MSH5 showed protective associations, while AHI1 showed cell-type-dependent, bidirectional associations across immune lineages. Colocalization and independent cohort evaluation supported these findings. Among FDR-significant multi-SNP associations, MR-Egger intercept tests did not indicate directional pleiotropy, although a small subset showed heterogeneity or MR-PRESSO signals. Phenome-wide analyses identified no significant adverse phenotypic associations among evaluable genes at the prespecified threshold. DrugBank annotation nominated sodium nitroprusside, fasudil, artenimol, and choline as hypothesis-generating compounds for experimental follow-up. CONCLUSIONS: This study provides a single-cell genetic framework for prioritizing immune-cell-specific candidate targets for EBV-related phenotypes and MS, and nominates genetically supported targets and pharmacologic hypotheses for experimental investigation.

Humans↗

PubMed2026

Genetic dissection of cardiac iron regulation using transcriptome network analysis and systems genetics in BXD mice.

Cardiac iron homeostasis is essential for myocardial energy metabolism and contractile function, yet the genetic and molecular mechanisms governing iron levels within the heart remain poorly understood. We used a systems genetics approach to dissect the transcriptional regulation of cardiac iron homeostasis. Myocardial iron level varies substantially across BXD strains (40-112 μg/g) and is under heritable genetic control (H2 = 0.38). Elevated cardiac iron is associated with reduced ventricular mass, increased ventricular ectopy, and prolonged atrioventricular conduction in the BXD population. Weighted gene co-expression network analysis of the BXD heart transcriptome identified a co-expression module that was significantly and negatively correlated with cardiac iron levels in both young and old BXD mice and enriched for pathways related to metabolic regulation, cyclic AMP (cAMP) signaling, circadian entrainment, and cardiovascular physiology. The module showed substantial overlap with a curated cardiac iron gene set, and cross-species enrichment analysis confirmed its conservation in human cardiomyopathy differentially expressed genes (enrichment ratio = 1.49; false discovery rate [FDR] = 0.0342). Quantitative trait locus (QTL) mapping of the first principal component of the overlapping module iron genes (n = 38), corroborated by individual gene mapping, identified trans-eQTL hotspots on multiple chromosomes, implicating Fcho2, Gcc2, and Rmdn1 as candidate upstream regulators operating through sequential steps of intracellular iron trafficking. Together, these findings establish a systems-level map of cardiac iron gene regulation, identify candidate genetic regulators, and provide a molecular framework linking disruption of iron-related transcriptional networks to structural and electrical cardiac dysfunction with implications for iron-related heart diseases.

BXD mouse population↗

PubMed1979

[Population genetics of the population of the northern European RSFSR. III. Demographic and genetic characteristics of two rural communities of the Pinezhskii District of the Arkhangel'sk Region].

The paper deals with the distribution of genetic markers (systems ABO, Rh, Hp, PTC) and a number of phenotyping traits (folding of arms, hand clasping, tongue rolling, right- and left-handedness, the type of ear lobe, the types of dermatoglyphics patterns) in the inhabitants of 5 villages in the Pinezhsky district of the Arkhangelsky region of the RSFSR. The data presented in this work were obtained in the course of examination of over 900 persons. Among the systems analysed there was a statistically significant deviation from Hardy-Weinberg's equlibrium. It took place in two the least villages. In one case--for ABO blood groups, in another--for Hp system. There are an interesting fact of the excess of heterozygotes 2-1 and some excess of the group 0. Statistically significant differences between villages were shown for four genetic systems. Data on migrations, distribution of gene frequencies and estimated genetic and phenotype distances between villages of the same village community and between two communities suggest, that each village community can be considered as separate subdivided population. Considering the uniformity of the environmental pressure in the region examined, the heterogeneity of the population studied is apparently associated with a random genetic drift.

Blood Group Antigens↗

PubMed1976

Genetic counseling. An evaluation of public health genetic clinics.

The geographic distribution of County Health Department clinic facilities in the state of California has made it readily possible to establish a regionalized program for genetic counseling services, using public health nurses as a major source of case-finding. From both consumer and health professional standpoints, regionalized satellite genetic counseling clinics have been successful, and in particular, the effectiveness of public health nurses in identifying clinical genetic problems is readily apparent.Long-term follow-up reinforcement of genetic counseling appears to be an important conclusion from these studies. It is our suggestion that reinforcement of counseling would best be accomplished through the health team member (physician, nurse and so forth) following the patient or family rather than through the consulting geneticist.

Adult↗

PubMed2025

Clinical and genetic variant re-analysis among pediatric probands undergoing genetic testing for arrhythmia syndromes.

BACKGROUND: Despite increases in genetic testing, longitudinal data regarding changes in diagnostic yield and variant reclassification for inherited arrhythmia syndromes are limited. OBJECTIVE: Determine longitudinal changes in diagnostic yield and variant classification. METHODS: Single-center retrospective study of probands <18 years undergoing genetic testing for suspected inherited cardiac conditions associated with arrhythmias, 2007 to 2018. Variants were classified as diagnostic (pathogenic/likely pathogenic), non-diagnostic (benign/likely benign [B/LB]), or variants of uncertain significance (VUS). Variant reclassification was performed in October 2023 using VarSome and American College of Medical Genetics criteria. We evaluated results by era (early 2007-2013 vs. later 2014-2018, coinciding with Sanger and next-generation sequencing, respectively) and by likelihood of disease based on clinical evaluation. RESULTS: Of 306 probands, initial testing was 23.2% diagnostic, 55.6% non-diagnostic (33.7% no variant, 21.9% B/LB), and 21.2% VUS. When comparing eras, diagnostic yield decreased (34.1%-15.3%), VUS increased (9.3%-29.9%), and non-diagnostic remained similar (55% to 57%). Variants for 22.7% (46/203) of probands with ≥1 variant changed: 9.9% of diagnostic variants (7/71) downgraded to VUS or non-diagnostic, and 60.0% of VUS changed (23.1% upgraded, 36.9% downgraded). B/LB variants did not change. Probands with higher disease likelihood had 6-times the odds of diagnostic results compared to lower disease likelihood, regardless of era (odds ratio 6.3, 95% confidence interval 3.2-12.4, P < .0001). CONCLUSION: Variant reclassification led to changes in 23% of probands, both downgrading and upgrading status, even among probands initially thought to be pathogenic. When comparing later to earlier eras, VUS variants increased while diagnostic yield decreased. Findings support the need for variant re-interpretation and periodic reclassification over time.

Humans↗

PubMed1976

Genetic studies of coliphage P1. III. Extended genetic map.

An extensive genetic map of coliphage P1 has been constructed for 113 amber mutants, using primarily a modification of the conventional complementation spot test. These spot tests failed to classify the mutants into cistrons, but when they were quantitated they permitted assignment of the mutants into 10 linkage clusters. Furthermore, a linear order could be deduced for most of the mutants within each cluster. This strongly suggested that recombination was the predominant event generating plaques and that, for the practical purpose of rapid genetic mapping, such spot tests could be considered as a series of two-factor crosses. Six of the 10 linkage clusters correlated with the P1 genetic map established by Scott (1968). The locations of the remaining four clusters were determined by three-factor crosses and by prophage deletion mapping. The nonrandom occurrence of termini for 14 deletion prophages, which we established previously (Walker and Walker, 1975), and the coincidence of these termini with five out of ten regions demarcating the linkage clusters are discussed. Complementation tests in liquid frequently gave ambiguous results. Therefore, cistron designations were not assigned.

Chromosome Mapping↗

PubMed1976

Genetics of affective disorders. II. Morbidity risk and genetic transmission.

Morbidity risk and genetic transmission data on a small population of bipolar, unipolar and schizo-affective outpatients suggest a possible genetic overlap between bipolar and schizo-affective patients. There is a conspicuous absence of a homologous illness in the relatives of schizo-affective probands, although the incidence of schizophrenia was higher in these relatives as compared to the relatives of either bipolar or unipolar probands. The data, although tentative because of the relatively small numbers involved, suggest a multifactorial mode of transmission in some affective illnesses. These disease entities appear familial rather than 'genetically transmitted'. There are select families who show the heritable genetic penetrance previously recorded for these mental disorders.

Adult↗

PubMed1976

[Genetic-statistical analysis of multiple births in humans. I. Genetic analysis of predisposition to multiple birth].

Genetico-statistical analysis was made to check various hypotheses of the tendency to multiple birth inheritance. The material involved was comprised of 115 MZ and 228 DZ twin families burdened by recurrent cases of multiple births in their genealogy. Test data included 516 single birth probands, 5 from which had twins among sibs; this results in p = 0,97% for the evaluation of population frequency of the "affected" couples having twins). Vienberg proband method was applied to check monogenous-autosomal model and Edward & Smith approximating formulae to check additive-polygenous model with liminal results (manifestation). It is shown: 1) that the degree of genetical determination of MZ and DZ twinning is approximately the same for both multiple birth types; H-61 and 53% respectively; 2) in MZ twinning both mother's and father's genotypes perform as multiple birth factors; H-76% for the group of mother's sisters and 64% for that of father's brothers; 3) in case of DZ twinning mother's genotype is much more valid as a multiple birth factor as compared to the father's one; H-68% for the group of mother's sisters and H-25% for father's brothers; 4) at least some genetical factors, involved in multiple birth determination, are common for MZ and DZ twins; the rate of DZ twinning (of different sexes) among sibs of parents of MZ twins is reliable and more than 5-fold increases that in common population. It is suggested that the contradiction of literary data on multiple birth genetics is due to unadequate methods in many early investigations: calculations have been carried out on the basis of twin birth rate, and not on the rate of "affected" (couples having twins); differential Veinberg's method has been used, which is adequate in populational analysis and is unsuitable for genealogical studies for the estimation of MZ and DZ twinning frequency; cases of "sporadic" multiple birth have not been excluded from summary family material. On the basis of the authors' and literary data it is suggested also that the number of main genetic factors determining the tendency to multiple births is more than 2 (probably 3) and does not exceed 5, and their interaction approximated by oligenic-complementary model, which does not exclude the presence of genocopying loci in a total system.

Adolescent↗

PubMed1979

Genetic and physical characterization of a segment of yeast mitochondrial DNA involved in the control of genetic recombination.

Genetic recombination between the 3 RIB (ribosomal) loci of yeast mitochondrial DNA is under the control of a mitochondrial locus named omega (with alleles omega+ and omega-) which is tightly linked to the RIBI locus. We have attempted to elucidate the molecular mechanisms(s) involved by using rho- mutants with similar (RIBI+ RIB2+ RIB3(0) genotype but different recombination properties in rho- x rho+ crosses. These were obtained through pedigree analysis and their mitochondrial DNAs were mapped on a high resolution physical map of the RIB section that had been built by analysis of thermal denaturation profiles and electron microscopy of partially denatured molecules. By comparison of physical and genetic data it can be shown that possession of the omega+ allele by the rho- cell is not sufficient for its expression in crosses, some additional DNA segments(s) in the ribosomal region being needed. This result and several features of the rho+ x rho- crosses are discussed in the light of current concepts in mitochondrial genetics of yeast and the recently discovered fact that omega+ and omega- strains differ by the presence of a 1000 base pairs insertion in the former.

Base Sequence↗

PubMed2026

Genetic architecture of postpartum psychosis: from common to rare genetic variation.

Postpartum psychosis is a severe psychiatric condition marked by the abrupt onset of psychosis, mania, or psychotic depression following childbirth. Despite evidence for a strong genetic basis, the roles of common and rare genetic variation remain poorly understood. Leveraging data from Swedish national registers and genomic data from the All of Us Research Program, we estimated family-based heritability at 55% and whole-genome sequencing-based heritability at 46%. Rare coding variant analysis identified HMGCR as a gene in which rare damaging variants confer risk for postpartum psychosis (FDR < 0.05). Analyses of 240,009 participants from the All of Us Research Program and 58,990 participants from the Mount Sinai BioMe Biobank identified significant associations linking deleterious rare variants in HMGCR to vascular dementia and mental disorder, not otherwise specified, supporting the gene's broader psychiatric relevance. Additionally, among the top 200 genes ranked by association statistics, 17% of bipolar disorder, 21% of schizophrenia, and 16-25% of multiple autoimmune disorders exhibit a possible association with postpartum psychosis. These findings reveal unique genetic contributions and shared pathways, providing a foundation for understanding pathophysiology and advancing therapeutic strategies.

Humans↗

PubMed1977

Genetic studies of the Macushi and Wapishana Indians. II. Data on 12 genetic polymorphisms of the red cell and serum proteins: gene flor between the tribes.

Blood samples from 509 Macushi (3 villages) and 623 Wapishana (11 villages) of Northern Brasil and Southern Guyana have been analyzed with respect to the phenotype and gene frequencies at the following 12 polymorphic loci: ABO, Kell-Cellano, MNSs, Rh, P, Duffy, Kidd, Diego, Lewis, Group-specific component, and the immunoglobulin allotypes of the Gm and Inv systems. The data suggest that 5-6% of the Wapishana gene pool is derived from non-Indians but only 1-2% of the Macushi. Inter- and intratribal genetic distances between villages are calculated for these data in an effort to understand gene flow between the tribes and to account for the unusual distribution of a newly-discovered genetic polymorphism of erythrocyte esterase A thus far limited to these 2 tribes (Neel et al., 1977). The data are puzzling and consistent with the possibility that both the Carib-speaking Macushi and the Arawak-speaking Wapishana have derived the esterase A allele in question from some third group now extinct or thus far undiscovered. Intertribal genetic distances based on gene frequencies at 6 loci are derived for 20 Amerindian tribes (including these 2); the "central" position of these 2 tribes can in part be explained by the active migration matrix connecting them.

ABO Blood-Group System↗

PubMed1976

[Relationship between genetic differentiation of the thymus in mice of different strains and malignant growth. IV. Genetic analysis of the thymic index in mice].

Relative thymus weight was estimated in C3H/He, C57BL/6 mice, their F1 and backcross hybrids, as well as in the progeny of complete diallel crosses between the BALB/c, C3H/He, C57BL/6 and AKR/J strains. On the basis of the analysis of these measurements, a conclusion is drawn that this character is inherited with incomplete dominance of smaller relative weight. The genes determining greater thymus weight are concentrated in the genetic pool of AKR/J and C57BL/6 strains. These genes are characterized by some degree of recessivity with respect to the genes determining smaller thymus weight which are concentrated in the genetic pool of C3H/He and BALB/c strains. The highest concentration of the "plus" and "minus" genes is found in the genetic pools of AKR/J and C3H/He strains respectively.

Animals↗

PubMed1975

Role of DNA sequences in genetic recombination in the iso-1-cytochrome c gene of yeast. I. Discrepancies between physical distances and genetic distances determined by five mapping procedures.

Recombination rates have been examined in two-point crosses of various defined cyc1 mutants using five mapping methods. Nucleotide sequences of mutant codons were identified in previous studies from alterations in functional iso-1-cytochromes c produced by intragenic revertants. Heteroallelic diploids were analyzed for rates of mitotic recombination that occurred spontaneously and that were induced with x-rays, ultraviolet light and the near-ultraviolet light emitted by sunlamps, as well as rates of meiotic recombination that occur after sporulation. Frequencies of both mitotic and meiotic recombination do not necessarily correspond with physical distances separating altered nucleotides. The most extreme discrepancy involved two adjacent intervals of thirteen basepairs which differed approximately thirty-fold in their spontaneous and X-ray-induced recombination rates. Marked disproportions between genetic and physical distances appear to be due to the interaction of the two nucleotide sequences in the heteroallelic combination and not to the sequences of the mutant codons alone. Recombination values that were obtained by all five methods could not be used to establish to correct order of mutant sitesmrelationships of the recombination rates for the various pairwise crosses are different after mitosis from those after meiosis, suggesting that these two recombinational processes are to some extent different in their dependence on particular nucleotide configurations. On the other hand, the relationships of the rates induced by UV-, sunlamp- and X-irradiation were identical or very similar. In addition to the intrinsic properties of the alleles affecting frequencies of mitotic and meiotic recombination rates, two- to threefold variations in recombination rates could be attributed to genetic backgrounds.

Base Sequence↗

PubMed2025

Noninvasive preimplantation genetic testing for aneuploidy using blastocyst spent culture medium may serve as a backup of trophectoderm biopsy in conventional preimplantation genetic testing.

BACKGROUND: To investigate whether the noninvasive preimplantation genetic testing (niPGT) complement conventional preimplantation genetic testing (PGT) in the embryos for aneuploidy. RESULTS: 40 spent culture medium (SCM) samples from routine embryo culture were collected, and half of each SCM (10 µL) sample was used for whole genome amplification, while the other half was stored at -80 °C for 3-6 months. Thirty-six out of 40 fresh SCM samples were successfully amplified and sequenced. Thirty-six paired frozen-thawed SCM samples showed 100% concordance with the freshly amplified SCM samples. Then, SCM and trophectoderm (TE) samples from 149 blastocysts from 51 couples were collected. A 98.0% successful SCM sample amplification rate (146/149) was achieved. For the 146 paired TE biopsy and SCM samples, the overall concordance rate was 82.9% (121/146). Ten embryos with aneuploid TE results but euploid niPGT results were donated. A 70.0% (7/10) true negative rate was achieved by niPGT with respect to the inner cell mass (ICM) results (TE-positive embryos). CONCLUSIONS: These results suggested that SCM stored at -80 °C for 6 months without affecting niPGT results based on NICSInst amplification.

Humans↗

PubMed2025

Leveraging local ancestry and cross-ancestry genetic architecture to improve genetic prediction of complex traits in admixed populations.

The broader application of polygenic risk score (PRS) is hindered by the limited transferability of PRS developed in Europeans to non-European populations. While many statistical methods have been developed to improve the performance of PRS in non-European populations, most of them focused on discrete genetic ancestry clusters and did not consider admixed individuals. Admixed individuals pose a unique challenge for PRS calculation due to the complexity of local ancestry and cross-ancestry effect sizes. Here, we present a statistical method called SDPR_admix for calculating PRS in admixed individuals. SDPR_admix characterizes the joint distribution of the effect sizes of a genetic variant with two ancestries to be both zero, ancestry enriched, or shared with correlation. SDPR_admix outperformed other methods in simulations and improved the prediction of real traits in European-African admixed individuals in UK Biobank when trained on the Population Architecture using Genomics and Epidemiology (PAGE) dataset (N = 13,000). Deployment of SDPR_admix on All of Us (N = 52,000) further increased the prediction accuracy by approximately 5-fold on average compared with training on PAGE. This enhancement was achieved with manageable computational time and cost, demonstrating the feasibility of training PRS models on large-scale All of Us data. We provided several examples demonstrating that both ancestral-enriched and shared effects, as included in the SDPR_admix prediction model, are helpful for improving polygenic prediction in admixed populations. We also applied SDPR_admix to construct PRS for admixed Americans with mixture of European and Amerindigenous ancestries and showed that SDPR_admix overall outperformed other methods.

Humans↗