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PubMed2005

Fishing for pleiotropic QTLs in a polygenic sea.

The application of factor analysis to human genetics has the potential to discover the coordinated control of multiple traits by common environment, common polygenes, or a single major gene. Classical factor analysis explains the covariation among the components of a random vector by approximating the vector by a linear transformation of a small number of uncorrelated factors. In the current paper we show how factor analysis dovetails with the classical variance decompositions of biometrical genetics. To explore the relationships between related quantitative variables, and avoid complicated positive definiteness constraints, we employ Cholesky and factor analytic decompositions. We derive an ECM algorithm and a competing quasi-Newton algorithm for estimating parameters by maximum likelihood and propose tactics for selecting initial parameter values. We also show how parameter asymptotic standard errors under these parameterizations propagate to asymptotic standard errors of the underlying variance components. Our genetic analysis program Mendel, which now incorporates the program Fisher, has performed well on a variety of data sets. We illustrate our methods, algorithms, and models on two data sets: a bivariate quantitative genetic example using total finger ridge count data and a multivariate linkage example using insulin resistance data.

Algorithms↗

PubMed1977

Evidence for polygenic inheritance in schizophrenia?

The frequency of psychotics among sibs of index cases with a functional psychosis was found by Odegaard (1972) to be positively associated with the number of psychotics in the parents' generation. Odegaard considered this correlation to be indicative of polygenic inheritance. However, an attempt at replicating this fascinating finding in a sample of schizophrenic families was not successful. Although this discrepancy in results might have been due to chance, the importance of the problem of the mode of inheritance induced a search for biases that might have obscured the comparison of the two samples. Unfortunately, the discrepancy remained unexplained, but certain structural and diagnostic differences were brought up and discussed. The very existence of such incongruities, together with the contrasting main results, seems to caution against definite genetic conclusions until further evidence is available.

Female↗

PubMed1993

Evidence for additive polygenic control of pupation height in Drosophila ananassae.

In order to study the mode of inheritance of pupation height in Drosophila ananassae, two mass culture stocks derived from ecogeographically different localities in India, were used to make a complete set of 16 crosses, which include parentals, F1, backcrosses, and F2. Pupation height defined as the distance a larva pupates over the surface of culture medium was scored in all 16 crosses. The two parental lines showed significant difference in pupation height. The F1 larvae in both reciprocal crosses had intermediate pupation height and there was no difference between two reciprocal crosses as well as between F1 and mid parent value. However, there was greater variance in the F2 generation. These findings provide evidence that the inheritance of pupation height fits a classical additive polygenic model and suggested that there is substantial amount of additive genetic variation in natural populations of D. ananassae. Furthermore, the analysis of reciprocal backcrosses shows significant maternal effect. Progeny with low pupating mothers showed lower pupation height than those with low pupating fathers and progeny with high pupating mothers had higher pupation height than those with high pupating fathers. Since the maternal effect was found only in backcrosses but not in the F1, it is suggested that this maternal effect on pupation height follows the pattern of inheritance of a transient maternal effect.

Animals↗

PubMed1977

Histocompatibility antigens and genetic control of the immune response in guinea-pigs. V. Evidence from further breeding studies for the polygenic control of the cellular immune response to structurally unrelated antigens in the guinea-pig.

Further breeding studies were carried out to investigate the polygenic control of the cellular immune response in the guinea-pig to low doses of aspirin anhydride (ASAN), penicilloylated bovine immunoglobulin (BPO-BGG) and to the multi-chain copolymer (T, G)-A-L. Although responsiveness to these three antigens is controlled by three independently segregating loci, at least one gene required for these responses is linked to the strain 13 haplotype.

Animals↗

PubMed1982

Genetic parameters of the polygenic regulation of antibody responsiveness to flagellar and somatic antigens of salmonellae.

Selective breedings of mice were carried out for quantitative antibody responsiveness to flagellar Ag., f (Selection III) or somatic Ag., s (Selection IV) of two non cross-reacting Salmonellae (Salm. tm., Salm. or.) alternated for immunization of consecutive generations. At the selection limit, these selections produced homozygous high (H) and low (L) responder lines for the character investigated: peak agglutinin response to optimal secondary immunization. The responsiveness to both f and s Ags. is submitted to polygenic regulation. The heritability (h2) realized during the selective breeding was 0.37 +/- 0.07 for the response to fAg. and 0.40 +/- 0.1 for the response to s Ag. The respective part of genetic and environmental variance in F2 hybrids was 64% and 36% in selection III and 61% and 39% in selection IV. In the two selections, the dominance variance is negligible (less than 1%), therefore the genetic variance is essentially additive. The additive variance calculated as the heritable fraction of the F2 hybrid variance is somewhat lower, the reason for this difference is discussed. The quantitative antibody response to f Ag. in selection III is controlled by about seven independent loci. The antibody response to s Ag. in selection IV is controlled by about four independent loci. A possible association of relevant genes with the H-2 locus was investigated. In selection III, no significant participation if H-2 linked genes, in the regulation of responses to f and s Ags. of Salm. tm and Salm. or. could be demonstrated. In selection IV a partial contribution of H-2 linked genes was observed concerning responsiveness to both f and s Ags. of Salm. tm. but not Salm. or. Ags. The H-2 effect accounts for 25% of the total interline difference.

Agglutinins↗

PubMed2003

Determinants of the host range restriction of replication of bovine parainfluenza virus type 3 in rhesus monkeys are polygenic.

The Kansas strain of bovine parainfluenza virus type 3 (BPIV3) is 100- to 1,000-fold restricted in replication in the respiratory tracts of nonhuman primates compared to human PIV3 (HPIV3), an important pathogen of infants and young children. BPIV3 is also restricted in replication in human infants and children, yet it is immunogenic and is currently being evaluated in clinical trials as a vaccine candidate to protect against illness caused by HPIV3. We have examined the genetic basis for the host range attenuation phenotype of BPIV3 by exchanging each open reading frame (ORF) of a recombinant wild-type HPIV3 with the analogous ORF from BPIV3, with the caveats that the multiple ORFs of the P gene were exchanged as a single unit and that the HN and F genes were exchanged as a single unit. Recombinant chimeric bovine-human PIV3s were recovered from cDNA, and the levels of viral replication in vitro and in the respiratory tract of rhesus monkeys were determined. Recombinant chimeric HPIV3s bearing the BPIV3 N or P ORF were highly attenuated in the upper and lower respiratory tracts of monkeys, whereas those bearing the BPIV3 M or L ORF or the F and HN genes were only moderately attenuated. This indicates that the genetic determinants of the host range restriction of replication of BPIV3 for primates are polygenic, with the major determinants being the N and P ORFs. Monkeys immunized with these bovine-human chimeric viruses, including the more highly attenuated ones, developed higher levels of HPIV3 hemagglutination-inhibiting serum antibodies than did monkeys immunized with BPIV3 and were protected from challenge with wild-type HPIV3. Furthermore, host range determinants could be combined with attenuating point mutations to achieve an increased level of attenuation. Thus, chimeric recombinant bovine-human PIV3 viruses that manifest different levels of attenuation in rhesus monkeys are available for evaluation as vaccine candidates to protect infants from the severe lower respiratory tract disease caused by HPIV3.

Animals↗

PubMed2026

Hypertrophic cardiomyopathy: a genome-wide association meta-analysis and polygenic risk score.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a heritable trait with marked variability in expression and outcomes. Our aims were to discover new genetic loci associated with HCM and to test the effect of a new polygenic risk score (PRS) on incidence, phenotype and outcomes stratified by genotype status. METHODS: A discovery genome-wide association study (GWAS) was performed on 2284 HCM cases and 4525 controls. Two fixed-effects meta-analyses combined our discovery GWAS with single-trait and multi-trait results from a published study. Discovered loci underwent comprehensive bioinformatic analysis including functional and druggability annotations. A PRS using loci from the two meta-analyses was evaluated for association with HCM diagnosis in 411 213 individuals from UK Biobank (UKBB); imaging phenotypes in individuals without HCM; a composite endpoint (including all-cause mortality and transplantation); and sudden cardiac death (SCD) in 1756 HCM cases. PRS analyses were stratified by genotype status. RESULTS: Three loci were found in the discovery GWAS (BAG3, FHOD3 and novel locus PPP1R3A). In the meta-analyses, 70 unique loci were identified, four novel (MYPN, YWHAE, NOS1AP and OBSCN). Bioinformatic analyses identified NOS1AP as a candidate HCM gene. A new PRS was significantly associated with HCM diagnosis (HR=3.19, 95% CI 2.46 to 4.14 for top 5% vs lower 95%; HR=1.88, 95% CI 1.72 to 2.06 per SD increase). Significant associations were found between PRS and greater left ventricular (LV) wall thickness and higher LV ejection fraction in UKBB participants without HCM. Genotype-negative HCM cases in the top 20% of the PRS distribution had an increased risk of SCD (HR=2.72, 95% CI 1.03 to 7.17). CONCLUSIONS: We report novel HCM loci. A new PRS predicted the risk of HCM development and associated imaging characteristics in the UKBB and outcomes in an HCM cohort.

Cardiomyopathies↗

PubMed1996

Human type 1 diabetes and the insulin gene: principles of mapping polygenes.

We review the strategy used to identify a susceptibility locus (IDDM2) for type 1 (insulin dependent) diabetes mellitus. As type 1 diabetes is becoming the paradigm for dissecting multifactorial disease genetics, the approach described provides important general guidelines for positional cloning of human disease polygenes. Main topics include: (a) historical conspectus of the mapping and identification of IDDM2--a critical survey of the work leading up to the conclusion that IDDM2 most likely corresponds to allelic variation at the insulin gene minisatellite (VNTR) locus; (b) the nature of allelic (length and sequence) variation at the VNTR locus; (c) gene interactions and disease pathogenesis; (d) mechanism of action of the INS VNTR in type 1 diabetes--insulin gene expression, parent-of-origin effects (genomic imprinting); and (e) summary and future prospects--alleles of the insulin VNTR that are protective for type 1 diabetes appear to encode susceptibility to type 2 diabetes.

Alleles↗

PubMed2000

Polygenic and multifactorial disease gene association in man: Lessons from AIDS.

In an age when the majority of monogenic human disease genes have been identified, a particular challenge for the coming generation of human geneticists will be resolving complex polygenic and multifactorial diseases. The tools of molecular and population genetic association have much potential as well as peril in uncovering small cryptic genetic effects in disease. We have used a candidate gene approach to identify eight distinct human loci with alleles that in different ways influence the outcome of exposure to HIV-1, the AIDS virus. The successes in these gene hunts have validated the approach and illustrate the strengths and limitations of association analysis in an actual case history. The integration of genetic associations, well-described clinical cohorts, extensive basic research on AIDS pathogenesis, and functional interpretation of gene connections to disease offers a formula for detecting such genes in complex human genetic phenotypes.

Acquired Immunodeficiency Syndrome↗

PubMed2005

Functional genomic characterization of delipidation elicited by trans-10, cis-12-conjugated linoleic acid (t10c12-CLA) in a polygenic obese line of mice.

Gene expression was measured during t10c12-CLA-induced body fat reduction in a polygenic obese line of mice. Adult mice (n = 185) were allotted to a 2 x 2 factorial experiment consisting of either nonobese (ICR-control) or obese (M16-selected) mice fed a 7% fat, purified diet containing either 1% linoleic acid (LA) or 1% t10c12-CLA. Body weight (BW) by day 14 was 12% lower in CLA- compared with LA-fed mice (P < 0.0001). By day 14, t10c12-CLA reduced weights of epididymal, mesenteric, and brown adipose tissues, as a percentage of BW, in both lines by 30, 27, and 58%, respectively, and increased liver weight/BW by 34% (P < 0.0001). Total RNA was isolated and pooled (4 pools per tissue per day) from epididymal adipose (days 5 and 14) of the obese mice to analyze gene expression profiles using Agilent mouse oligo microarray slides representing > 20,000 genes. Numbers of genes differentially expressed by greater than or equal to twofold in epididymal adipose (days 5 and 14) were 29 and 125, respectively. It was concluded that, in adipose tissue, CLA increased expression of uncoupling proteins (1 and 2), carnitine palmitoyltransferase system, tumor necrosis factor-alpha (P < 0.05), and caspase-3 but decreased expression of peroxisome proliferator-activated receptor-gamma, glucose transporter-4, perilipin, caveolin-1, adiponectin, resistin, and Bcl-2 (P < 0.01). In conclusion, this experiment has revealed candidate genes that will be useful in elucidating mechanisms of adipose delipidation.

Animals↗

PubMed2025

Evaluation of Multiple Breast Cancer Polygenic Risk Score Panels in Women of Latin American Heritage.

BACKGROUND: A substantial portion of the genetic predisposition for breast cancer is explained by multiple common genetic variants of relatively small effect. A subset of these variants, which have been identified mostly in individuals of European (EUR) and Asian ancestries, have been combined to construct a polygenic risk score (PRS) to predict breast cancer risk, but the prediction accuracy of existing PRSs in Hispanic/Latinx individuals (H/L) remain relatively low. We assessed the performance of several existing PRS panels with and without addition of H/L-specific variants among self-reported H/L women. METHODS: PRS performance was evaluated using multivariable logistic regression and the area under the ROC curve. RESULTS: Both EUR and Asian PRSs performed worse in H/L samples compared with original reports. The best EUR PRS performed better than the best Asian PRS in pooled H/L samples. EUR PRSs had decreased performance with increasing Indigenous American (IA) ancestry, while Asian PRSs had increased performance with increasing IA ancestry. The addition of two H/L SNPs increased performance for all PRSs, most notably in the samples with high IA ancestry, and did not impact the performance of PRSs in individuals with lower IA ancestry. CONCLUSIONS: A single PRS that incorporates risk variants relevant to the multiple ancestral components of individuals from Latin America, instead of a set of ancestry-specific panels, could be used in clinical practice. IMPACT: The results highlight the importance of population-specific discovery and suggest a straightforward approach to integrate ancestry-specific variants into PRSs for clinical application.

Adult↗

PubMedDate not supplied

Mapping genes for polygenic disorders: considerations for study design in the complex trait of inflammatory bowel disease.

While the methodology for the mapping of Mendelian disorders is well established, the practical and theoretical steps required for successful gene identification in a complex trait are still difficult to predict. A number of analytical models and simulations based on repetitive drawings from predefined statistical distributions are available. To supplement these analytical models, we developed an integrated simulation approach by directly simulating entire populations under a disease model based on epidemiological data. Random mating, nonoverlapping populations and the absence of differential fitness were assumed. Samples were drawn from these homogeneous and heterogeneous populations and analyzed with established analysis tools. We investigated the properties of linkage and association studies in inflammatory bowel disease - modeled as a six-locus polygenic disorder - as an example of this approach. In nonparametric linkage studies, lod scores varied widely, with the median required sample size depending on the locus-specific relative sibling risk. A fine mapping resolution <4 cM was found to require nonparametric lod scores >10. Family-based association studies (TDT test) and case-control studies showed a similar sensitivity and can identify risk loci in populations with moderate levels of linkage disequilibrium in sample sizes of 500-800 triplets. Case-control association studies were prone to false-positive results if applied in heterogeneous populations, with the false-positive rate increasing with sample size because population heterogeneity is detected with increasing power.

Alleles↗

PubMed1975

Bilateral inheritance as evidence for polygenicity in functional psychoses.

Among 1,678 functional psychoses followed up, 35 had parents, uncles, aunts or grandparents with 2 or more cases diagnosed as schizophrenic psychoses, or 2 or more secondary relatives diagnosed as non-schizophrenic psychoses. Comparisons of unilateral and bilateral inheritance suggest that the schizophrenic and endogenous affective psychoses have polygenic transmission, while this is not the case for reactive psychoses.

Bipolar Disorder↗

PubMed1976

Estimation of polygenic recurrence risk for cleft lip and palate.

Data on cleft lip with or without cleft palate are utilized to evaluate a new method for estimating recurrence risk under the polygenic threshold model. The influence of critical factors on the accuracy of the estimated risks are evaluated. The model is relatively sensitive to the estimate of heritability employed and relatively robust to the population prevalence estimate and to family size. The calculated risks for cleft lip with or without cleft palate are contrasted with the empiric figures from studies on Caucasians and Japanese populations.

Cleft Lip↗

PubMed2026

Agnostic polygenic prediction of weight loss after bariatric surgery.

A large interindividual variability in weight loss outcomes following bariatric surgery is reported. To ensure optimal management of patients, it is crucial to accurately identify candidates most likely to benefit the most from the intervention. Since genetic variants largely contribute to surgery response, polygenic scores (PGS) derived from genome-wide association studies (GWAS) could constitute valuable tools for clinical decision making. We developed and evaluated PGS to predict the weight loss response in 540 patients with a body mass index (BMI) of 35 kg/m2 or higher who underwent biliopancreatic diversion with duodenal switch. Summary statistics derived from BMI-derived GWAS, together with summary statistics from previously published GWAS of BMI and adiposity features, were used to construct, evaluate, and benchmark weight loss PGS. The full-adjusted BMI PGS model built in the entire cohort explained 39.6% of the mean-over-time excessive body weight loss (%EBWL), while the BMI-PGS built in the training dataset explained 38.9%. All benchmarked PGS based on BMI showed a significant relationship with mean-over-time %EBWL. These findings highlight the potential of BMI PGS in predicting weight loss after bariatric surgery and support their use as promising tools to improve the effectiveness of future antiobesity treatments.

Humans↗

PubMed2026

Multi-trait polygenic scores for COPD and COPD exacerbations implicate druggable proteins.

BACKGROUNDWe constructed multi-trait polygenic risk scores (PRSs) predicting chronic obstructive pulmonary disease (COPD) and exacerbations, validated their performance in diverse cohorts, and identified PRS-related proteins for potential therapeutic targeting.METHODSPRSmix+, a multi-trait PRS framework, is used to train a composite PRS (PRSmulti) in COPDGene non-Hispanic White participants (n = 6,647). Associations of PRSmulti with COPD status (GOLD 2-4 vs. GOLD 0 or ICD) and exacerbation frequency were tested in COPDGene African American (n = 2,466), ECLIPSE (n = 1,858), Mass General Brigham Biobank (n = 15,152), and All of Us (n = 118,566). Protein prediction models were applied to GWAS summary statistics from traits contributing to PRSmulti and were validated with proteomic data in COPDGene (n = 5,173) and UK Biobank (n = 5,012).RESULTSPRSmix+ selected 7 traits for PRSmulti. In multivariable models, PRSmulti was associated with COPD status (meta-analysis random effects [RE] OR 1.58 [95% CI: 1.28-1.94]) and exacerbation frequency (meta-analysis RE β 0.21 [95% CI: 0.11-0.31]), with higher effect sizes observed in smoking-enriched cohorts. PRSmulti outperformed traditional single-trait PRS in all tested cohorts. Using protein prediction models, we identified 73 proteins associated with the PRSs that were also validated with measured protein levels in COPDGene and UK Biobank. Of these proteins, 25 were linked to approved or investigational drugs. Notable targets include RAGE/sRAGE, IL1RL1, and SCARF2, all implicated in COPD pathogenesis and exacerbations.CONCLUSIONSMulti-trait PRS improves prediction of COPD and exacerbation risk. Integration with proteomic data identifies druggable protein targets, offering a promising avenue for precision medicine in COPD management.TRIAL REGISTRATIONCOPDGene: ClinicalTrials.gov NCT00608764; ECLIPSE: ClinicalTrials.gov NCT00292552.

Humans↗

PubMedDate not supplied

Polygenic inheritance of otosclerosis.

A large family has been studied and its pedigree traced for six generations. Fifteen relatives are known to have had otosclerosis. Of these, the only six individuals who developed this disease before the age of twenty were offspring of second-cousin marriages. Other children in the extended family developed the disease later and may have had somewhat less severe symptoms. The original hypothesis that the severe, early onset cases occurred among those homozygous for a monogenic trait became improbable on mathematical analysis. We conclude that the inheritance of otosclerosis in this family is polygenic and probably multifactorial. Individuals marrying within the family have a greatly increased risk of giving birth to children who will develop otosclerosis early, and perhaps severly. Those who marry outside the family have a greatly decreased risk. They do, of course have a higher risk than the general population of having children who will at some point experience a conductive hearing loss.

Adult↗

PubMedDate not supplied

Hypodontia: a polygenic trait--a family study among Israeli Jews.

A high prevalence of hypodontia was detected among 820 first degree relatives of 305 probands and there was an increased risk if a second family member was affected. Hypodontia is a common trait in the population, and a deviation from normal sex ratio was observed in those affected. These results suggest a polygenic mode of inheritance.

Adolescent↗