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PubMed2004

A large-sample QTL study in mice: III. Reproduction.

Using lines of mice having undergone long-term selection for high and low growth, a large-sample (n approximately to 1000 F2) experiment was conducted to gain further understanding of the genetic architecture of complex polygenic traits. Composite interval mapping on data from 10-week-old F2 females (n = 439) detected 15 quantitative trait loci (QTLs) on 5 chromosomes that influence reproduction traits characterized at day 16 of gestation. These QTL are broadly categorized into two groups: those where effects on the number of live fetuses (LF) were accompanied by parallel effects on the number of dead fetuses (DF), and those free of such undesirable effects. QTL for ovulation rate (OR) did not overlap with QTL for litter size, potentially indicating the importance of uterine capacity. Large dominance effects were identified for most QTL detected, and overdominance was also present. The QTL of largest effects were detected in regions of Chromosome 2, where large QTL effects for growth and fatness have also been found and where corroborating evidence from other studies exists. Considerable overlap between locations of QTL for reproductive traits and for growth traits corresponds well with the positive correlations usually observed among these sets of phenotypes. Some support for the relevance of QTL x genetic background interactions in reproduction was detected. Traits with low heritability demand considerably larger sample sizes to achieve effective power of QTL detection. This is unfortunate as traits with low heritability are among those that could most benefit from QTL-complemented breeding and selection strategies in food animal production.

Animals↗

PubMed1991

Magnaporthe grisea genes for pathogenicity and virulence identified through a series of backcrosses.

We have identified genes for pathogenicity toward rice (Oryza sativa) and genes for virulence toward specific rice cultivars in the plant pathogenic fungus Magnaporthe grisea. A genetic cross was conducted between the weeping lovegrass (Eragrostis curvula) pathogen 4091-5-8, a highly fertile, hermaphroditic laboratory strain, and the rice pathogen O-135, a poorly fertile, female-sterile field isolate that infects weeping lovegrass as well as rice. A six-generation backcrossing scheme was then undertaken with the rice pathogen as the recurrent parent. One goal of these crosses was to generate rice pathogenic progeny with the high fertility characteristic of strain 4091-5-8, which would permit rigorous genetic analysis of rice pathogens. Therefore, progeny strains to be used as parents for backcross generations were chosen only on the basis of fertility. The ratios of pathogenic to nonpathogenic (and virulent to avirulent) progeny through the backcross generations suggested that the starting parent strains differ in two types of genes that control the ability to infect rice. First, they differ by polygenic factors that determine the extent of lesion development achieved by those progeny that infect rice. These genes do not appear to play a role in infection of weeping lovegrass because both parents and all progeny infect weeping lovegrass. Second, the parents differ by simple Mendelian determinants, "avirulence genes," that govern virulence toward specific rice cultivars in all-or-none fashion. Several crosses confirm the segregation of three unlinked avirulence genes, Avr 1-CO39, Avr 1-M201 and Avr1-YAMO, alleles of which determine avirulence on rice cultivars CO39, M201, and Yashiro-mochi, respectively. Interestingly, avirulence alleles of Avr1-CO39, Avr1-M201 and Avr1-YAMO were inherited from the parent strain 4091-5-8, which is a nonpathogen of rice. Middle repetitive DNA sequences ("MGR sequences"), present in approximately 40-50 copies in the genome of the rice pathogen parent, and in very low copy number in the genome of the nonpathogen of rice, were used as physical markers to monitor restoration of the rice pathogen genetic background during introgression of fertility. The introgression of highest levels of fertility into the most successful rice pathogen progeny was incomplete by the sixth generation, perhaps a consequence of genetic linkage between genes for fertility and genes for rice pathogenicity. One chromosomal DNA segment with MGR sequence homology appeared to be linked to the gene Avr1-CO39. Finally, many of the crosses described in this paper exhibited a characteristic common to many crosses involving M. grisea rice pathogen field isolates.(ABSTRACT TRUNCATED AT 400 WORDS)

Ascomycota↗

PubMed2002

First model of spontaneous vagal hyperreactivity and its mode of genetic transmission.

BACKGROUND: The main purpose of our study was to define an animal model of vagal hyperreactivity and its genetic transmission. METHODS AND RESULTS: We first investigated the vagal reactivity with phenylephrine in conscious rabbits. Barosensitivity and the maximal bradycardic response were measured at the upper mean blood pressure plateau. Hyperreactive (H) animals were selected and crossbred with normal (N) ones. Results showed no significant difference between calculated barosensitivity values after the different doses of phenylephrine. In contrast, an increase of the values and a great dispersion appeared 1 to 5 beats after the end of the ramp. Marked pauses (6000 to 20 000 ms) were obtained with some rabbits, which were blocked by atropine. A significant excess of hyperreactive offspring was observed in HxH crossings compared with NxN ones (39.4% male and 42.3% female offspring versus 14.4% and 4.4%, respectively). Few female offspring were hyperreactive compared with males in NxH and NxN crossings (4.1% versus 23.4% and 4.4% versus 14.4%, respectively). CONCLUSIONS: This study describes the first model of spontaneous vagal pauses. The inheritance could be polygenic with a partial sex-limited character.

Animals↗

PubMed1997

Clinical aspects on the use of preimplantation genetic diagnosis in couples at risk.

BACKGROUND: Preimplantation genetic diagnosis (PGD) is a new technique which may become an attractive alternative to traditional prenatal diagnosis for couples at risk of getting children with severe genetic diseases. We here report our experience after the first trials in Sweden. METHODS: On day three after fertilization by intracytoplasmic sperm injection (ICSI) one or two blastomeres were biopsied and diagnosed by fluorescence in situ hybridization (FISH). Gender determination was done in two cases where the female in the couples were carrier of a severe X-chromosome bound disease (Wiskott-Aldrich disease or ornithine transcarbamylase deficiency). RESULTS: The first couple got an embryo transfer in each of their two treatment cycles. Two female embryos were transferred in the first cycle and one in the second cycle. The second couple did not get any embryo transfer in their two cycles. No clinical pregnancy occurred. CONCLUSION: With the rapidly improving knowledge about inherited disease and refinement of the IVF techniques, PGD will play an important clinical role in high risk groups within a decade for both mono- and polygenic disorders. Both technical as well as legal and ethical problems have however to be solved before these new techniques can be applied on large scale.

Embryonic Development↗

PubMed2000

Mapping quantitative trait loci for serum insulin-like growth factor-1 levels in mice.

Serum insulin-like growth factor-1 (IGF-1) and femoral bone mineral density (BMD) differ between two inbred strains of mice, C3H/HeJ (C3H) and C57BL/6J (B6), by approximately 30% and 50%, respectively. Similarly, skeletal IGF-1 content, bone formation, mineral apposition, and marrow stromal cell numbers are higher in C3H than in B6 mice. Because IGF-1 and several bone parameters cosegregate, we hypothesize that the serum IGF-1 phenotype has a strong heritable component and that genetic determinants for serum IGF-1 are involved in the regulation of bone mass. We intercrossed (B6 x C3H)F1 hybrids and analyzed 682 F2 female offspring at 4 months of age for serum IGF-1 by radioimmunoassay and femoral BMD by peripheral quantitative computerized tomography (pQCT). Genomic DNA was assayed by polymerase chain reaction (PCR) to determine alleles for 114 Mit markers inherited in F2 mice at average distances of 14 centimorgans (cM) along each chromosome (Chr). Serum IGF-1 levels in the F2 progeny were relatively normal in distribution, but showed a greater range than either progenitor, indicating that serum IGF-1 level is a polygenic trait with an estimated heritability of 52%. Serum IGF-1 correlated with femoral length (r = 0.266, p < 0.0001) and femoral BMD (r = 0.267, p < 0.0001). Whole genome scans for main effects associated with serum IGF-1 levels revealed three significant QTLs (in order of significance) on mouse Chrs 6, 15, and 10. The QTL on Chr 6 showed a significant reduction in IGF-1 associated with increasing C3H allele number, whereas the Chr 15 and Chr 10 loci showed additive effects with increasing C3H allele number. A genome-wide search for interacting marker pairs identified a significant interaction between the Chr 6 QTL and a locus on Chr 11. This interactive effect suggested that when the Chr 11 locus was homozygous for C3H, there was no effect of the Chr 6 locus on serum IGF-1; however, the combination of C3H alleles on Chr 6 with B6 alleles on Chr 11 was associated with reduced serum IGF-1 concentrations. To test this in vivo, we tested congenic mice carrying the Chr 6 QTL region from C3H on a B6 background (B6.C3H-6). Both serum IGF-1 and femoral BMD were significantly lower in female congenic than progenitor B6 mice. In summary, we identified three major QTLs on mouse Chrs 6, 10, and 15, and noted a major locus-locus interaction between Chrs 6 and 11. We named these QTLs IGF-1 serum levels (Igf1sl1 to Igf1sl4). Functional isolation of the Igf1sl1 QTL on Chr 6 for IGF-1 in B6.C3H-6 congenic mice demonstrated effects on both the IGF-1 and BMD phenotypes. The genetic determinants of these Igf1sl QTLs will provide much insight into the regulation of IGF-1 and the subsequent acquisition of peak bone mass.

Animals↗

PubMed2003

The Sgp3 locus on mouse chromosome 13 regulates nephritogenic gp70 autoantigen expression and predisposes to autoimmunity.

By interval mapping of a backcross progeny between New Zealand White (NZW) and C57BL/6 (B6) mice bearing the Y chromosome-linked autoimmune acceleration gene Yaa, we previously identified a genetic locus on mid-chromosome 13, here designated as Sgp3, showing a major effect on the expression of a nephritogenic autoantigen, gp70. In this study, the NZW-derived Sgp3 region was transferred by backcross procedure and marker-assisted selection on the B6 background to produce three independent congenic strains B6.NZW-Sgp3/1, -Sgp3/2, and -Sgp3/3. We show that NZW homozygosity at a single 3 centiMorgans ( approximately 12 megabases (Mb)) interval between markers D13Mit142 and D13Mit254 mediates increased basal serum levels of gp70 in B6.NZW-Sgp3/1 and B6.NZW-Sgp3/2 mice and with a higher degree in males ( approximately 15 micro g/ml) than in females ( approximately 9 micro g/ml) as compared with B6 ( approximately 2 micro g/ml), revealing a gender effect. However, their gp70 levels are still lower than that of NZW mice ( approximately 60 micro g/ml). In addition, B6.NZW-Sgp3/1 and B6.NZW-Sgp3/2 mice showed a moderate 2- to 3-fold increase in serum gp70 in response to LPS, which contrasted with over a 10-fold increase in NZW mice. Although both B6.NZW-Sgp3/1 and B6.NZW-Sgp3/2 mice failed to produce significant amounts of gp70 anti-gp70 immune complexes, unexpectedly, aged B6.NZW-Sgp3/2 congenic males bearing the Yaa gene developed increased titers of IgG autoantibodies to DNA and chromatin. Our data indicate that Sgp3 is involved in a complex process of gp70 production under polygenic control and may provide a significant contribution to lupus susceptibility not only through up-regulation of gp70 autoantigen production but also predisposition to autoimmunity.

Animals↗

PubMed2002

Endothelial dysfunction and blood pressure variability in selected inbred mouse strains.

The genetic regulation of blood pressure (BP) and endothelial function is likely to be polygenic. Because there is considerable variability in basal BP among inbred mouse strains, the purpose of this study was to determine whether a similar variability in vascular function exists among 7 "normotensive" strains. We tested the hypothesis that compared with mice with higher BPs, mice with lower BPs would have greater aortic endothelial responses to acetylcholine (ACh). Mean BP ranged from 117 to 145 mm Hg among the 7 strains. The responses of aortic rings to ACh, sodium nitroprusside, and papaverine were assessed after submaximal precontraction with prostaglandin F(2alpha). The aortas from all strains relaxed in a concentration-dependent manner to sodium nitroprusside and papaverine, but responses to ACh were markedly impaired in the aortas, but not carotid arteries, from 129P3/J and 129X1/SvJ mice. Aortas from the other strains relaxed normally to ACh. Furthermore, the endothelium-dependent dilators ADP and A23187 caused similar relaxation in 129P3/J, 129X1/SvJ, and C57BL/6J mice. Although the data do not support the initial hypothesis, the impaired aortic response to ACh in the 129 strains is a novel finding and illustrates the potential impact that genetic background can have on vascular responsiveness.

Acetylcholine↗

PubMed2026

Familial lymphoma and genetic predisposition: an updated review.

BACKGROUND: Several factors contribute to the development of malignant lymphomas including environmental exposures, bacterial and viral infections, as well as familial and genetic factors. MAIN BODY: Numerous somatic variants are involved in lymphomagenesis, and an increasing number of germline variants predisposing patients to lymphoid neoplasm have been identified. Although most lymphomas arise sporadically, epidemiological studies have linked a familial history of lymphomas and other hematological tumors with an increased lymphoma risk. Although rare, familial clustering of malignant lymphoma is well documented, and the constellations suggest inherited risk factors. Recent technological advancements have improved our ability to identify genetic factors associated with lymphoma that overall lead to a better understanding of genetic susceptibility for these entities. In this context, we here provide a comprehensive perspective on lymphoma risk factors to support improved lymphoma risk assessment and testing. A dedicated clinical management could influence future advances in lymphoma therapies and might also prevent severe toxicity and secondary malignancies. However, to date, only few susceptibility genes for malignant lymphomas have been identified. Highly penetrant mutations in known genes cannot account for most of the excess in a polygenic and heterogenic disease such as cancer. High-throughput sequencing identifies pathogenic variants that may constitute most low-penetrance alleles. However, their detection requires many well-characterized cases and controls. In this review, we therefore also include a short discussion on a Swiss cohort where we prospectively collect and samples for genetic data from individuals with a family history of lymphoma. We are convinced that such an approach is more informative and feasible than a population-based project with unselected cases and aim to better inform both genetic counsellors and oncologists. CONCLUSION: Inherited genetic factors contribute to lymphoma risk in a subset of patients. Improved identification of susceptibility variants, particularly through family-based studies, may enhance risk assessment and inform personalized clinical management.

Humans↗

PubMed2004

Genetic variation in the multifunctional transcription factor Yy1 and type 1 diabetes mellitus in the BB rat.

Spontaneous diabetes in B(io)B(reeding) rats is complex, polygenic, and recessively inherited. Several crossing studies have demonstrated that beside the class II genes of the major histocompatibility complex (MHC, Iddm1) additional non-MHC genes are involved in diabetes development. One of them, Iddm4, was initially mapped on chromosome 6q32. To study the physiologic importance of Iddm4 a congenic BB.SHR rat strain (BB.6S) was established. The BB.6S is characterised by a drastic reduction of diabetes frequency (86 vs. 14%) indicating existence of diabetes protective genes of SHR on the exchanged chromosomal segment. One of the possible diabetes susceptibility candidate genes located within this exchanged region is the multifunctional transcription factor Yin yang 1 (Yy1). Yy1 was therefore sequenced in BB/OK and SHR rats. No genetic variation in exons between BB/OK and SHR was found. However, three single nucleotide polymorphisms (SNPs) were detected in intron 4. To determine the "wild type" allele, intron 4 of several diabetes-resistant inbred rat strains (DA, LEW, BN, and WOKW) and wild rats was sequenced. In addition, a congenic BB/OK strain was established by introgressing the same segment of chromosome 6 (D6Rat184-D6Rat3) of wild rats onto BB/OK background (BB.6W). The sequence analysis showed the SNP pattern of SHR (A/C/C) in all inbred rat strains studied whereas both unrelated wild rats showed the pattern of BB/OK rats (T/G/A). The congenic BB.6W rats developed diabetes in the same extent than BB/OK rats. This finding may support the assumption that the SNP pattern of BB/OK and wild rats favours and that of SHR suppresses diabetes development. Because of strong synteny between rat chromosome 6q32 and human 14q32, Yy1 may be also of interest in human type 1 diabetics showing significant linkage to markers on chromosome 14q32.

Animals↗

PubMed1986

Genetic variability of flight metabolism in Drosophila melanogaster. III. Effects of Gpdh allozymes and environmental temperature on power output.

The effect of allozyme variation at the sn-glycerol-3-phosphate dehydrogenase (Gpdh) locus on variation in the mechanical power output of the flight muscles of Drosophila melanogaster was investigated. The influence of different rearing and flight temperatures and of their interactions with the Gpdh allozymic genotypes (allotypes) on flight ability also were analyzed. Populations from three continents were used, and Gpdh allotypes were generated from crosses between randomly paired isofemale lines made autozygous for each of the two alleles by inbreeding. Measurements made during tethered flight, together with wing morphology, were used to estimate power output using both Weis-Fogh's and Ellington's formulas. Analyses of variance (ANOVA) indicated significant main effects for both environmental components (rearing and flight temperatures) but for only one of the three genetic components (genetic backgrounds within continent); Gpdh allotypes and populations (continent of origin) were not significant. The interaction between rearing and flight temperature was highly significant, indicating some physiological adaptation. The effect of Gpdh allozymes depended on both rearing and flight temperature and was either significant or marginally so, depending on which set of formulas was used. In either case, the S/S allotype showed a 2-4% greater power output than the F/F allotype at low temperature for both interactions. In addition, the S/S allotype showed significantly greater power output than the F/F allotype among flies raised at 15 degrees and flown at 15 degrees, whereas the reverse was true for flies raised at 30 degrees and flown at 30 degrees. Significant differences among the three allotypes for GPDH activity level were found in general, with S/S having the highest, F/S intermediate and F/F the lowest activity, and an inverse relationship existed between rearing temperature and activity. The temperature effects on power output are consistent with the geographical and seasonal variation observed at the Gpdh locus in nature. In general, the results show that Gpdh can be considered a minor polygene affecting quantitative variation in the power output during flight and that genotype-by-environment interaction is an important component of that effect.

Alleles↗

PubMed1982

Diabetes-obesity syndromes in mice.

Several different rodent models are available for metabolic studies on the development of diabetes. Although the abnormalities associated with each diabetes type have many features in common, the documentation of several different genes being involved makes it unlikely that the various syndromes will be reduced to a single disturbance in one metabolic pathway. The severity of the diabetes produced depends on the interaction of the individual mutation with genetic factors in the inbred background of the host. Establishing the nature of these gene-host interactions in rodents should aid us in understanding similar interactions that occur in human diabetes. The development of the syndrome in most models is similar and includes hyperinsulinemia, hyperphagia, and attempts at increasing insulin supply by beta-cell hyperplasia and hypertrophy in the early stages. Hyperglycemia, obesity, and severe diabetes are secondary features that result from a combination of insulin resistance and a failure to sustain the secretion of the large amounts of insulin. Most models utilize ingested food and stored food reserves more efficiently. This increased metabolic efficiency extends to heterozygotes that are normal in all respects having only one dose of the deleterious gene. Establishing this increased metabolic efficiency in heterozygotes lends credence to the thrifty gene hypothesis of diabetes and suggests a mechanism whereby some deleterious diabetes genes may be favored in the human population. The best studied mouse models, and those for which the most complete information is available, are those caused by single genes, e.g., yellow, obese, diabetes, tubby, and fat. In the other models, the mode of inheritance is either polygenic or otherwise unclear, features which interfere with the interpretation of the data. This report briefly summarizes the developing syndrome in each model, points out any differences, and suggests the most appropriate areas where future research should be most productive in the light of contemporary studies.

Animals↗

PubMed2003

Genetics of human hypertension.

BACKGROUND: Hypertension is a multifactorial disease involving interactions among genetic, environmental, demographic, vascular and neuroendocrine factors. Essential hypertension is the most frequent diagnosis in this syndrome, indicating that a monocausal etiology has not been identified. However, a number of risk factors underlying essential hypertension have also been identified including age, sex, genetics, demographic factors, and others. Remarkable progress in molecular biological research has been achieved in clarifying the molecular basis of Mendelian hypertensive disorders. Causative genes and chromosomal fragments harboring disease susceptibility genes have been identified, e. g., for glucocorticoid-remediable aldosteronism, Liddle's syndrome, mineralocorticoid excess. MOLECULAR GENETIC STUDIES: Molecular genetic studies have now identified mutations in eight genes that cause Mendelian forms of hypertension and nine genes that cause Mendelian forms of hypotension in humans. No single genetic variant has emerged from linkage or association analyses as consistently related to blood pressure level in every sample and in all populations. However, a number of polymorphisms in candidate genes have been associated with differences in blood pressure. Most prominent have been the polymorphisms in the renin-angiotensin-aldosterone system. CONCLUSION: Essential hypertension is likely to be a polygenic disorder that results from the inheritance of a number of susceptibility genes and involves multiple environmental determinants. These determinants complicate the study of blood pressure variations in the general population. The complex nature of the hypertension phenotype makes large-scale studies indispensable, when screening of familial and genetic factors is intended.

Chromosome Mapping↗

PubMed2026

Linkage between HLA-B8 and HLA-DQ2.5 Contributes to Ancestry-Dependent Genetic Risk for Celiac Disease.

BACKGROUND: Most genetic studies on celiac disease (CeD) have focused on individuals of European descent. Limited data are available for the Hispanic and black populations. METHODS: We analyzed whole-genome sequencing data, electronic health records (EHR), and laboratory results from the All of Us Research Program. We identified 3,481 individuals with CeD through EHR, self-reporting, or both. Of these, 2,899 carried one of the four well-established risk haplotypes, including 262 of admixed American (89% Hispanic) and 108 of African (70% black) ancestry. Five sex-, age-, and ancestry-matched controls per case were selected for the assessment of genetic and clinical risk factors. RESULTS: An enrichment in the DQB1*02:01 allele was observed in CeD patients across all ancestries, with the strongest association in Europeans (32.3% vs. 11.6%), followed by Americans (18.5% vs. 8.1%) and Africans (15.7% vs. 8.1%). Among individuals carrying the DQ2.5 (DQA1*05:01-DQB1*02:01 haplotype), HLA-B8 was present in 72.3% of Europeans, 42.3% of Admixed Americans, and lower in Africans. This linkage disequilibrium was higher in CeD patients than in controls across all three ancestries. A polygenic risk score distinguished seropositive CeD from controls with 86% accuracy. Incorporating clinical risk factors, including family history, hypothyroidism, diarrhea, vitamin D deficiency, and anemia, increased predictive accuracy to 92%. The model identified 93% of CeD patients with tTG-IgA levels greater than 10 IU/mL. CONCLUSION: Linkage between HLA-B8 and DQ2.5 differs significantly among individuals of European, admixed American, and African ancestry, contributing to ancestry-dependent genetic risk for CeD.

Celiac disease↗

PubMed2000

[Molecular genetics of essential hypertension. Susceptibility and resistance genes].

Essential Hypertension (EH) is a multifactorial and polygenic syndrome with a high impact in public health. Recently, rare mendelian forms of hypertension such as glucocorticoid-remediable aldosteronism (GRA), apparent mineralocorticoid excess (AME) and Liddle Syndrome caused by single gene mutations have been identified in which the mechanism is an increased sodium retention. Therefore, it is tempting to speculate that the most common forms of EH may be due to diverse highly prevalent molecular variants of susceptibility genes with low penetrance that are involved in arterial blood pressure (ABP) and electrolytic balance. Although a number of candidate genes such as NO synthases, ANP, ion transporters, adducins, LDL receptor, etc. can participate, renin-angiotensin system components are the most extensively studied. Although not associated with EH, the ACE D allele seems to confer a high risk of CHD or LVH. Angiotensinogen 235T and 174M variants are more likely associated with EH and positively correlate with clinical or ambulatory ABP in adolescents or adults. Individuals who carry these angiotensinogen alleles would be at 1.4 higher risk of suffering EH than homozygotes for M235 or T174 alleles. Associations of AT1 receptor variants with EH remain to be definitively defined. In conclusion, the characterization of the genetic background, although difficult at the present time, may have clear benefits in terms of defining a more rational therapy and prevention in individuals at risk. Even though this aim seems difficult to achieve since more than 150 candidate genes have been postulated as the cause of EH, with 6 to 10 SNPs in each of them, new technologies such as DNA micro-arrays will provide us with the opportunity to analyse the total genetic risk in each subject.

Adolescent↗

PubMed2024

Polycystic Ovary Syndrome Physiologic Pathways Implicated Through Clustering of Genetic Loci.

CONTEXT: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder, with disease loci identified from genome-wide association studies (GWAS) having largely unknown relationships to disease pathogenesis. OBJECTIVE: This work aimed to group PCOS GWAS loci into genetic clusters associated with disease pathophysiology. METHODS: Cluster analysis was performed for 60 PCOS-associated genetic variants and 49 traits using GWAS summary statistics. Cluster-specific PCOS partitioned polygenic scores (pPS) were generated and tested for association with clinical phenotypes in the Mass General Brigham Biobank (MGBB, N = 62 252). Associations with clinical outcomes (type 2 diabetes [T2D], coronary artery disease [CAD], and female reproductive traits) were assessed using both GWAS-based pPS (DIAMANTE, N = 898,130, CARDIOGRAM/UKBB, N = 547 261) and individual-level pPS in MGBB. RESULTS: Four PCOS genetic clusters were identified with top loci indicated as following: (i) cluster 1/obesity/insulin resistance (FTO); (ii) cluster 2/hormonal/menstrual cycle changes (FSHB); (iii) cluster 3/blood markers/inflammation (ATXN2/SH2B3); (iv) cluster 4/metabolic changes (MAF, SLC38A11). Cluster pPS were associated with distinct clinical traits: Cluster 1 with increased body mass index (P = 6.6 × 10-29); cluster 2 with increased age of menarche (P = 1.5 × 10-4); cluster 3 with multiple decreased blood markers, including mean platelet volume (P = 3.1 ×10-5); and cluster 4 with increased alkaline phosphatase (P = .007). PCOS genetic clusters GWAS-pPSs were also associated with disease outcomes: cluster 1 pPS with increased T2D (odds ratio [OR] 1.07; P = 7.3 × 10-50), with replication in MGBB all participants (OR 1.09, P = 2.7 × 10-7) and females only (OR 1.11, 4.8 × 10-5). CONCLUSION: Distinct genetic backgrounds in individuals with PCOS may underlie clinical heterogeneity and disease outcomes.

Humans↗

PubMed2006

High-density single nucleotide polymorphism screen in a large multiplex neural tube defect family refines linkage to loci at 7p21.1-pter and 2q33.1-q35.

BACKGROUND: Neural tube defects (NTDs) are considered complex, with both genetic and environmental factors implicated. To date, no major causative genes have been identified in humans despite several investigations. The first genomewide screen in NTDs demonstrated evidence of linkage to chromosomes 7 and 10. This screen included 44 multiplex families and consisted of 402 microsatellite markers spaced approximately 10 cM apart. Further investigation of the genomic screen data identified a single large multiplex family, pedigree 8776, as primarily driving the linkage results on chromosome 7. METHODS: To investigate this family more thoroughly, a high-density single nucleotide polymorphism (SNP) screen was performed. Two-point and multipoint linkage analyses were performed using both parametric and nonparametric methods. RESULTS: For both the microsatellite and SNP markers, linkage analysis suggested the involvement of a locus or loci proximal to the telomeric regions of chromosomes 2q and 7p, with both regions generating a LOD* score of 3.0 using a nonparametric identity by descent relative sharing method. CONCLUSIONS: The regions with the strongest evidence for linkage map proximal to the telomeres on these two chromosomes. In addition to mutations and/or variants in a major gene, these loci may harbor a microdeletion and/or translocation; potentially, polygenic factors may also be involved. This single family may be promising for narrowing the search for NTD susceptibility genes.

Chromosomes, Human, Pair 2↗

PubMed1993

The genetic background of individual variations of circadian-rhythm periods in healthy human adults.

As a group phenomenon, human variables exhibit a rhythm with a period (tau) equal to 24 h. However, healthy human adults may differ from one another with regard to the persistence of the 24-h periods of a set of variables' rhythms within a given individual. Such an internal desynchronization (or individual circadian dyschronism) was documented during isolation experiments without time cues, both in the present study involving 78 male shift workers and in 20 males and 19 females living in a natural setting. Circadian rhythms of sleep-wake cycles, oral temperature, grip strength of both hands, and heart rate were recorded, and power-spectra analyses of individual time series of about 15 days were used to quantify the rhythm period of each variable. The period of the sleep-wake cycle seldom differed from 24 h, while rhythm periods of the other variables exhibited a trimodal distribution (tau = 24 h, tau > 24 h, tau < 24 h). Among the temperature rhythm periods which were either < 24 h or > 24 h, none was detected between 23.2 and 24 h or between 24 and 24.8 h. Furthermore, the deviations from the 24-h period were predominantly grouped in multiples of +/- 0.8 h. Similar results were obtained when the rhythm periods of hand grip strength were analyzed (for each hand separately). In addition, the distribution of grip strength rhythm periods of the left hand exhibited a gender-related difference. These results suggested the presence of genetically controlled variability. Consequently, the distribution pattern of the periods was analyzed to elucidate its compatibility with a genetic control consisting of either a two-allele system, a multiple-allele system, or a polygenic system. The analysis resulted in structuring a model which integrates the function of a constitutive (essential) gene which produces the exact 24-h period (the Dian domain) with a set of (inducible) polygenes, the alleles of which, contribute identical time entities to the period. The time entities which affected the rhythm periods of the variables examined were in the magnitude of +/- 0.8 h. Such an assembly of genes may create periods ranging from 20 to 28 h (the Circadian domain). The model was termed by us "The Dian-Circadian Model." This model can also be used to explain the beat phenomena in biological rhythms, the presence of 7-d and 30-d periods, and interindividual differences in sensitivity of rhythm characteristics (phase shifts, synchronization, etc.) to external (and environmental) factors.

Adult↗

PubMed2003

Analysis of polymorphisms affecting immune complex handling in systemic lupus erythematosus.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a polygenic disorder of dysregulated inflammation. Numerous specific candidate genes have been identified and most relate to the handling of immune complexes or antigen presentation. This is consistent with the classic finding of immune complex deposition in affected end organs. We wished to examine combinatorial effects of polymorphic variants of genes involved in immune complex clearance in susceptibility to lupus. METHODS: This study examined the occurrence of polymorphisms in genes which encode proteins known to be involved in immune complex handling and clearance. Each polymorphic variant of a complement protein (C2, mannose binding protein and C4), complement receptor (CR1) or Fc receptor (FcgammaRIIA and FcgammaRIIIA) gene is known to affect function adversely. One hundred and sixty SLE patients and 212 control subjects were genotyped using polymerase chain reaction methods. RESULTS: We found an increasing association of SLE with increasing numbers of gene defects. Combinations of severe defects in FcgammaRIIA and FcgammaRIIIA were particularly deleterious for both African American and Caucasian patients, even though only one defective variant was individually statistically significantly associated with SLE. CONCLUSIONS: The results of the study suggest that genes may interact in ways that either synergize or modify the effect of a single genetic effect and imply that association studies must be interpreted within the genetic background of the populations.

Antigen-Antibody Complex↗