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Results for “Genetic Heterogeneity”

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At least 19 recordsLinked to original sources
PubMed2026

Genetic heterogeneity affects the risk of incident depression, comorbidity, and response to environment: A prospective trajectory study.

BACKGROUND: Depression exhibits significant heterogeneity in its genetic underpinnings. The role of genetic components in the development of depression and its comorbidities remains insufficiently explored. METHODS: First, depression risk loci from a large-scale genome-wide meta-analysis were annotated to Gene Ontology (GO) terms by functional enrichment. GO-based polygenic risk scores (GO-PRS) were then calculated for individuals in the UK Biobank. Principal component analysis (PCA) was applied for dimensionality reduction, followed by cluster analysis to identify genetic subtypes of depression. Multistate models were applied to assess the impact of genetic patterns on the trajectory from healthy status to incident depression, and depression to 26 subsequent diseases, as well as the associations between environmental factors and disease trajectories across genetic subtypes. RESULTS: Participants were categorized into three genetic subtypes: immune-dominant, neuro-dominant, and comprehensive-risk. Significant differences in risk of depression and subsequent diseases, and susceptibility to environmental factors were observed across subtypes. Comprehensive-risk subtype showed higher risks of depression compared to immune-dominant (HR: 1.10, 95% CI: 1.05-1.15) and neuro-dominant subtype (HR: 1.12, 95% CI: 1.08-1.16). Comprehensive-risk subtype exhibited higher risks of transition from depression to subsequent diseases, such as anemia compared to immune-dominant subtype, and diseases of the digestive system compared to neuro-dominant subtype. Environmental factors were more strongly associated with the transition from depression to subsequent diseases in immune-dominant and comprehensive-risk subtypes, including cardiovascular, respiratory, and metabolic diseases. CONCLUSIONS: Our findings highlight the genetic heterogeneity of depression and comorbidities, and shed light on how genetic components modulate responses to environmental factors.

Humans↗
PubMed1978

Heterogeneity in diabetes mellitus--update, 1978. Evidence for further genetic heterogeneity within juvenile-onset insulin-dependent diabetes mellitus.

The concept that idiopathic diabetes mellitus is a genetically heterogeneous group of disorders has been established by twin and HLA studied that have permitted the separation of juvenile-onset and maturity-onset diabetes. The extent of the heterogeneity within the juvenile-onset and maturity-onset types is still in question. On the basis of recent immunologic and metabolic studies we believe that further heterogeneity can be demonstrated within the juvenile-onset diabetic group. We wish to hypothesize that there are at least two distinct forms of juvenile-onset diabetes, one associated with HLA B8 and the other with BW15. The B8 type is characterized by autoimmunity, microangiopathy, and a stronger association with the HLA D locus. The BW15 type is characterized by antibody response to exogenous insulin and a stronger association with the HLA C locus. Greater understanding of the pathogenesis, natural history, and genetics of diabetes mellitus will result as the full extent of genetic heterogeneity is elucidated.

Alleles↗
PubMed1979

Genetic heterogeneity of hyperpepsinogenemic I and normopepsinogenemic I duodenal ulcer disease.

In a search for a genetic marker of duodenal ulcer, we measured serum pepsinogen I levels in 168 ulcer patients and 151 of their clinically normal siblings. The ulcer patients tended to have either hyperpepsinogenemia I (pepsinogen I, greater than or equal to 100 ng/mL) or a normal level on a familial basis. Further evidence supporting this separation was the finding that the mean serum pepsinogen I level in the clinically normal siblings of the hyperpepsinogenemic patients was 91.2 ng/mL, significantly higher than the mean level (63.1 ng/mL) in the normal siblings of the normopepsinogenemic I patients. In the hyperpepsinogenemic I families the results of segregation analysis of an elevated pepsinogen I were consistent with autosomal-dominant inheritance of this trait. The genetic basis of normopepsinogenemic I duodenal ulcer was also shown by the familial aggregation of this disorder. These data provide direct evidence for genetic heterogeneity of duodenal ulcer disease.

ABO Blood-Group System↗
PubMed1978

Alpha1-antitrypsin: further genetic heterogeneity revealed by isoelectric focusing.

Alpha1-antitrypsin is a major human serum protein that shows an extensive polymorphism. Genetic heterogeneity has previously been demonstrated by starch gel electrophoresis. By applying analytical isoelectric focusing (pH 3.5--5.0) to this system, we found a common variant, Pi M3, with an isoelectric point between those of Pi M1 and Pi M2. The gene frequency of this variant was .11 in U.S. whites and .054 in blacks. When PiM3 and PiM1 are included in the Pi system, the heterozygosity at the Pi locus is five times greater in whites and 10 times greater in blacks than that detected by earlier electrophoretic techniques.

Black People↗
PubMed2026

Mitochondrial Haplotype Shapes the Trajectory of Ovarian Aging in Genetically Heterogeneous Rats.

Ovarian aging leads to permanent reproductive senescence and systemic hormonal changes that predispose women to age-associated comorbidities. Despite these observations, the intrinsic mechanisms driving age-related ovarian decline are poorly defined. Mitochondrial DNA (mtDNA) mutations and instability are strongly associated with aging; however, it remains unknown if naturally occurring mitochondrial genetic variation influences the trajectory of ovarian aging. To address this, we compared two genetically heterogeneous rat cohorts (OKC-HETB and OKC-HETW) that differ in mitochondrial haplotype on a randomized but equivalently distributed nuclear background. The OKC-HETW haplotype was associated with accelerated loss of primordial follicles and pathological remodeling marked by fibrosis, macrophage infiltration, and multinucleated giant cells. These tissue-level pathologies were paralleled by mitochondrial dysfunction, characterized by decreased respiratory complex activity, ATP production, and mtDNA copy number. Mechanistically, we identified a haplotype-specific defect in mitochondrial genome maintenance. Although TFAM expression was normal, and total TFAM protein was elevated, OKC-HETW ovaries showed reduced mitochondrial TFAM abundance, TFAM-mtDNA binding, and TOMM20, suggesting that impaired TOMM20-mediated import is associated with compromised mitochondrial genomic stability. Longitudinal transcriptomic and proteomic analyses further indicate that mitochondrial haplotype influences the rate of ovarian aging, with OKC-HETW ovaries showing accelerated activation of inflammatory and fibrotic pathways alongside suppressed proteostasis and mitochondrial function. These defects corresponded to impairments in ovulation and a trend toward worsening oocyte quality. Collectively, our findings identify mitochondrial haplotype as a heritable modifier of ovarian aging rate that acts in concert with the nuclear genome, and a putative target for preserving ovarian function and female healthspan.

Animals↗
PubMed2026

Genetic heterogeneity and pathogenic potential of historical Crimean-Congo hemorrhagic fever virus isolates in China.

The Crimean-Congo hemorrhagic fever virus (CCHFV) poses a significant public health threat. In China, CCHFV has been circulating for decades, yet the genomic diversity and pathogenic potential of the circulating strains remain poorly characterized, hindering risk assessment and countermeasure development. In this study, we recovered 24 historical CCHFV strains isolated between 1966 and 2004 from humans, ticks and jerboas in Xinjiang Uyghur Autonomous Region of China. Whole-genome sequencing was performed, followed by comprehensive analyses of their phylogenetic relationships, in vitro infectivity and in vivo pathogenicity. Phylogenetic analyses revealed high genetic heterogeneity, identifying seven genotypes for the L segment, nine for the M segment (including a novel Asia 4 genotype), and nine for the S segment. Amino acid mutation analysis revealed that the mucin-like domain (MLD) of the glycoprotein (GP) exhibited the highest mutation rate, contributing substantially to sequence diversity. In vitro, Asia 2 (75024) and Asia 3 (79121M18) strains exhibited robust replication in monkey-, hamster-, and human-derived cell lines. In C57BL/6 mice, all four representative strains induced viral replication and specific antibody responses (IgM and IgG), causing mild to moderate pathological damage in the liver, spleen, and kidneys. In IFNAR-/- mice, virulence varied markedly among representative strains: Asia 2 and Asia 3 strains were highly lethal (LD50 < 1 TCID50), Asia 1 was moderately virulent (LD50 = 142.5 TCID50), and Asia 4 exhibited atypical, non-dose-dependent mortality. Collectively, our work reports a novel Asia 4 genotype and suggests strain- and lineage-associated differences in virulence for CCHFV in China, providing critical insights for surveillance and targeted countermeasure development.

Animals↗
PubMed1979

Genetic heterogeneity of "normal" human erythrocyte glucose-6-phosphate dehydrogenase: an isoelectrophoretic polymorphism.

Quantitative determination of glucose-6-phosphate dehydrogenase (G6PD; D-glucose-6-phosphate: NADP+ 1-oxidoreductase, EC 1.1.1.49) activity was carried out in 214 male Nigerian children of 84 mothers with known Gd genotype. The relative intrasibship difference in G6PD activity (normalized to the lowest value within the sibship) was below 0.18 in all cases but one when the children were known to have the same Gd+ allele (identical by descent); whereas it was higher than 0.18 in 18 out of 33 sibships in which children might have had either of the two maternal (electrophoretically identical) Gd+ alleles. G6PD from 10 (8 G6PD B and 2 G6PD A) children belonging to four of the sibships possessing high quantitative variation in G6PD activity was partially purified and extensively characterized. The 8 G6PD type B samples fell unambiguously into two classes on the basis of Km values for glucose 6-phosphate (determined at variuos pH values), and KCl gradient elution from DEAE-Sephadex columns. The two types of G6PD B were resolved from an artificial mixture on a DEAE-Sephacel column. The two G6PD type A samples were also different from each other by the same criteria. We conclude that "normal" G6PD is genetically heterogeneous and that the structural Gd alleles concerned are all polymorphic in the Nigerian population. In this instance, a human enzyme polymorphism, not associated with enzyme deficiency, is revealed by an approach other than electrophoresis.

Alleles↗
PubMed2026

Genetic Heterogeneity of Inborn Errors of Immunity Revealed by Whole-Genome Sequencing: Insights from a Russian Patient Cohort.

Identifying genetic cause(s) is a key step for management and treatment of patients with inborn errors of immunity (IEI). Here, in an observational cross-sectional genomic study, we analyzed whole-genome sequencing (WGS) data of 72 IEI patients from Saint Petersburg and Northwestern Russia: 42 patients with common variable immunodeficiency (CVID)-like phenotypes, 6 patients with clinically diagnosed X-linked agammaglobulinemia (XLA or Bruton's disease), and 24 patients with other forms of IEI. Causative pathogenic and likely pathogenic variants in BTK, CYBB, CHD7, AIRE, ATM, SBDS, NFKB1, and CTLA4 genes were identified in 14 (19%) patients. Variants of uncertain significance that could be linked to observed clinical phenotypes were detected in 6 patients. These included a BTK variant in a patient with Bruton's disease, variants in SH2D1A, SOCS1, and IKBKB in patients with CVID, and variants in CARD11 and CD40LG in patients with other forms of IEI. Additional rare variants that were mostly unique to individual patients were found in multiple IEI genes from the International Union of Immunological Societies (IUIS) Expert Committee 2024 list. In the CVID-like subcohort, pathway-level analysis of these rare variants revealed patterns associated with clinical manifestations. Taken together, our results expand the genetic characterization of an understudied regional IEI cohort, particularly of patients with CVID-like phenotypes, and identify genetic factors that are implicated in or may contribute to the disease.

Humans↗
PubMed1977

Genetic heterogeneity within the chondroitinsulphaturias.

The approach, identification of clinical phenotype followed by lysosomal enzyme assays in cell culture, used in the classification of the genetic mucopolysaccharidoses I-VI has been applied to the chondroitinsulphaturias. There was evidence of heterogeneity in the first 9 patients reported.

Cells, Cultured↗
PubMed2025

Genetic heterogeneity in patients with enlarged vestibular aqueduct and Pendred syndrome.

BACKGROUND: Pathogenic variants in the SLC26A4 gene, encoding for Cl-/HCO3- and I- anion transporter pendrin, are associated with non-syndromic hearing loss with enlarged vestibular aqueduct (NSEVA) and Pendred syndrome (PDS). In the Caucasian population, up to 75% of patients fail to identify a genetic cause through biallelic mutations in the SLC26A4 gene. The CEVA haplotype could therefore play an important role in the diagnostics of NSEVA. The aim of the study was to determine the genetic etiology of hearing loss with EVA or with fully developed PDS in 37 probands and the functional characterization of novel variants identified in the SLC26A4 gene. METHODS: To determine the genetic etiology, Sanger sequencing, WES and KASP genotyping assay were used. Functional characterization of SLC26A4 variants c.140G>A (p.R47Q), c.415G>A (p.G139R), c.441G>A (p.M147I), c.481T>A (p.F161I), c.1589A>C (p.Y530S) and c.2260del (p.D754Ifs*5) involved determination of iodide influx, total and plasma membrane pendrin expression level and subcellular localization of pendrin by confocal imaging. The nanopore sequencing of nasopharyngeal swab samples was performed to confirm the pathogenic effect of potential splice site variant c.415G>A. RESULTS: Biallelic variants in the SLC26A4 gene (M2 genotype) were identified in ten probands and a complete CEVA haplotype was confirmed in three probands harbouring SLC26A4 monoallelic variants (M1 genotype). Fifteen variants in the SLC26A4 gene were identified in total, three of which are novel. The functional characterization of the novel variants and variants which were not yet functionally characterized confirmed the pathogenic potential of five out of six tested variants (p.G139R, p.M147I, p.Y530S, p.D754Ifs*5, and p.F161I). Analysis of nasopharyngeal swab samples confirmed exon 4 skipping due to novel variant SLC26A4:c.415G>A. Probands with biallelic SLC26A4 variants had significantly larger thyroid volume per m2 of body surface area than subjects with monoallelic SLC26A4 variants and the CEVA haplotype. CONCLUSIONS: The genetic aetiology was determined in 13 out of 37 probands (35%), seven manifested with PDS and six with NSEVA. The present study highlights the importance of functional testing to confirm the pathogenicity of SLC26A4 variants and the phenotype-genotype correlation in SLC26A4-related disorders.

Humans↗
PubMed1976

Androgen insensitivity in man: evidence for genetic heterogeneity.

We have studied ten phenotypically similar patients with complete androgen insensitivity. All of the patients tested had significantly elevated serum luteinizing hormone and plasma androgens within or above the normal adult male range. On the basis of specific dihydrotestosterone binding by skin fibroblasts, we identified two subgroups. Six patients from five different families had undetectable dihydrotestosterone binding, while four patients from two families had normal binding activity. Our results indicate that within the clinical syndrome of androgen insensitivity there are at least two distinct genetic variants. These variants may result from allelic mutations of the same X-linked gene specifying the dihydrotestosterone receptor or, alternatively, from mutations of separate genes both being essential for androgen action in responsive cells.

Androgen-Insensitivity Syndrome↗
PubMed1977

Variant of iduronidase deficient mucopolysaccharidoses: further evidence for genetic heterogeneity.

An alpha-L-iduronidase deficiency syndrome has been described in adult male twins, which was phenotypically distinct from that of the Hurler and Scheie syndromes or the chondroitinsulphaturias. Multiple dysostosis and stiff joints were present without cloudy corneae, cardiac involvement and mental or physical retardation. This clinical phenotype appeared to be a newly recognized allelic mutation at the iduronidase locus but does not exclude a non-allelic mutation coding for a subunit of the iduronidase molecule.

Adolescent↗
PubMed1975

Genetic heterogeneity in xeroderma pigmentosum: complementation groups and their relationship to DNA repair rates.

Fibroblast strains from 12 patients with xeroderma pigmentosum had lower than normal rates of DNA repair, as determined by autoradiographic studies of ultraviolet-induced unscheduled nuclear DNA synthesis. The nuclei in binuclear cells, obtained by fusing fibroblasts from certain pairs of these strains, had a greater rate of DNA repair than the nuclei of either strain's unfused mononuclear cells. These results indicate that complementary corrections of the strains' repair defects had occurred in the fused cells. Four complementation groups were found, indicating that at least four mutations caused decreased DNA repair among these 12 strains. The unfused mononuclear cells of each group had a characteristic rate of repair that differed from the rates of the other groups.

Autoradiography↗
PubMed1977

[Genetic heterogeneity of G6PD deficiency: mutant alleles of G6PD in the Shekii district of Azerbaijan].

Examination on G6PD deficiency in 349 patients of Shekii district hospital (Azerbaijan) revealed 16 hemi-, 4 homo- and 9 heterozygotic carriers of the defect. Gd- frequency, calculated from the data obtained (7.7%), may be compared to neighbouring regions' frequencies (6-30%). Carriers of G6PD deficiency are residents of 11 villages located in Alasani-Aphtalan valley, highly endemic with malaria in the past; nearly all marriages are endogamic. Physico-chemical and kinetic study of 10 mutant forms of G6PD, according to WHO program, led to identification of 5 variants of the II class (Shekii, Bideiz, Shirin-Bulakh, Okhut I and Zakataly) and 2 variants of the III class (Okhut II and Martinique-like). Resemblance of the majority of variants in electrophoretic mobility and the level of erythrocyte enzyme activity permit to suggest the existence of a common parental mutant G6PD allele distributed in this area.

Alleles↗