SEARCH · Search PubMed

Results for “polygenicity”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 703 records · Page 39Linked to original sources

PubMed2000

Genetics and ischaemic stroke.

Ischaemic stroke can be caused by a number of monogenic disorders, and in such cases stroke is frequently part of a multisystem disorder. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), due to mutations in the NOTCH: 3 gene, is increasingly appreciated as a cause of familial subcortical stroke. The genetics and phenotypes of monogenic stroke are covered in this review. However, the majority of cases of ischaemic stroke are multifactorial in aetiology. Strong evidence from epidemiological and animal studies has implicated genetic influences in the pathogenesis of multifactorial ischaemic stroke, but the identification of individual causative mutations remains problematic; this is in part limited by the number of approaches currently available. In addition, genetic influences are likely to be polygenic, and ischaemic stroke itself consists of a number of different phenotypes which may each have different genetic profiles. Almost all human studies to date have employed a candidate gene approach. Associations with polymorphisms in a variety of candidate genes have been investigated, including haemostatic genes, genes controlling homocysteine metabolism, the angiotensin-converting enzyme gene, and the endothelial nitric oxide synthase gene. The results of these studies, and the advantages and limitations of the candidate gene approach, are presented. The recent biological revolution, spurred by the human genome project, promises the advent of novel technologies supported by bioinformatics resources that will transform the study of polygenic disorders such as stroke. Their potential application to polygenic ischaemic stroke is discussed.

Animals↗

PubMed1996

Maximum likelihood analysis of rare binary traits under different modes of inheritance.

Maximum likelihood methodology was applied to determine the mode of inheritance of rare binary traits with data structures typical for swine populations. The genetic models considered included a monogenic, a digenic, a polygenic, and three mixed polygenic and major gene models. The main emphasis was on the detection of major genes acting on a polygenic background. Deterministic algorithms were employed to integrate and maximize likelihoods. A simulation study was conducted to evaluate model selection and parameter estimation. Three designs were simulated that differed in the number of sires/number of dams within sires (10/10, 30/30, 100/30). Major gene effects of at least one SD of the liability were detected with satisfactory power under the mixed model of inheritance, except for the smallest design. Parameter estimates were empirically unbiased with acceptable standard errors, except for the smallest design, and allowed to distinguish clearly between the genetic models. Distributions of the likelihood ratio statistic were evaluated empirically, because asymptotic theory did not hold. For each simulation model, the Average Information Criterion was computed for all models of analysis. The model with the smallest value was chosen as the best model and was equal to the true model in almost every case studied.

Algorithms↗

PubMed1998

Least squares interval mapping of quantitative trait loci under the infinitesimal genetic model in outbred populations.

Genetic marker and phenotypic data for a quantitative trait were simulated on 20 paternal half-sib families with 100 progeny to investigate properties of within-family-regression interval mapping of a postulated single quantitative trait locus (QTL) in a marker interval under the infinitesimal genetic model, which has been the basis of the application of quantitative genetics to genetic improvement programs, and to investigate use of the infinitesimal model as null hypothesis in testing for presence of a major QTL. Genetic effects on the marked chromosome were generated based on a major gene model, which simulated a central biallelic QTL, or based on 101 biallelic QTL of equal effect, which approximated the infinitesimal model. The marked chromosome contained 0, 3.3%, 13.3%, or 33.3% of genetic variance and heritability was 0.25 or 0.70. Under the polygenic model with 3.3% of genetic variance on the marked chromosome, which corresponds to the infinitesimal model for the bovine, significant QTL effects were found for individual families. Correlations between estimates of QTL effects and true chromosome substitution effects were 0.29 and 0.47 for heritabilities of 0.25 and 0.70 but up to 0.85 with 33.3% of polygenic variance on the marked chromosome. These results illustrate the potential of marker-assisted selection even under the infinitesimal genetic model. Power of tests for presence of QTL was substantially reduced when the polygenic model with 3.3% of genetic variance on the chromosome was used as a null hypothesis. The ability to determine whether genetic variance on a chromosome was contributed by a single QTL of major effect or a large number of QTL with minor effects, corresponding to the infinitesimal model, was limited.

Chromosome Mapping↗

PubMed1974

The genetic structure of natural populations of Drosophila melanogaster. XI. Genetic variability in a local population.

Six hundred and ninety-one second chromosomes were extracted from a Raleigh, North Carolina population, and the following experimental results were obtained: (1) Salivary gland chromosomes of all lines were observed and the number of inversion-carrying chromosomes was 130, among which 76 carried In(2R)NS, 36 carried In(2L)t, 4 carried In(2L)t and In(2R)NS, and 14 carried different kinds of rare inversions. (2) Viabilities of homozygotes and heterozygotes were examined. The frequency of lethal-carrying chromosomes was 275/691 (or 0.398):70/130 (or 0.538) in inversion-carrying chromosomes and 205/561 (or 0.365) in inversion-free chromosomes. The former is significantly higher than the latter. The average homozygote viability was 0.4342 including lethal lines and 0.7163 excluding those, the average heterozygote viability being 1.0000. The detrimental load to lethal load ratio (D:L ratio) was 0.334/0.501 = 0.67. The average viability of lethal heterozygotes was less than that of lethal-free heterozygotes, significantly in inversion-free individuals but not significantly so in inversion-carrying individuals. Inversion heterozygotes seem to have slightly better viability than the inversion-free heterozygotes on the average, but not significantly so. (3) The average degree of dominance of viability polygenes was estimated to be 0.293 +/- 0.071 for all heterozygotes whose component chromosomes had better viabilities than 0.6 of the average heterozygote viability, 0.177 +/- 0.077 for inversion-free heterozygotes and 0.489 +/- 0.082 for inversion heterozygotes. (4) Mutation rates of viability polygenes and lethal genes were estimated on the basis of genetic loads and average degrees of dominance of lethal genes and viability polygenes. Estimates were very close to those obtained by direct estimation. (5) Possible overdominance and epistasis were detected, but the magnitude must be very small. (6) The effective size of the population was estimated to be much greater than 10,000 by using the allelism rate of lethal-carrying chromosomes (0.0040) and their frequency.-On the basis of these findings and the comparison with the predicted result (Mukai and Maruyama 1971), the mechanisms of the maintenance of genetic variability in the population are discussed.

Adaptation, Biological↗

PubMed2001

Bayesian segregation analysis of production traits in two strains of laying chickens.

A bayesian marker-free segregation analysis was applied to search for evidence of segregating genes affecting production traits in two strains of laying hens under long-term selection. The study used data from 6 generations of Leghorn (H77) and New Hampshire (N88) breeding nuclei. Estimation of marginal posterior means of variance components and parameters of a single autosomal locus was performed by use of the Gibbs sampler. The results showed evidence for a mixed major gene: -polygenic inheritance of BW and age at sexual maturity (ASM) in both strains. Single genes affecting BW and ASM explained one-third of the genetic variance. For ASM large overdominance effect at single locus was estimated. Initial egg production (IEP) and average egg weight (EW) showed a polygenic model of inheritance. The polygenic heritability estimates for BW, ASM, IEP, and EW were 0.32, 0.25, 0.23, and 0.08 in Strain H77 and 0.25, 0.24, 0.11, and 0.38 in Strain N88, respectively.

Age Factors↗

PubMed2024

Distinguishing different psychiatric disorders using DDx-PRS.

Despite great progress on methods for case-control polygenic prediction (e.g. schizophrenia vs. control), there remains an unmet need for a method that genetically distinguishes clinically related disorders (e.g. schizophrenia (SCZ) vs. bipolar disorder (BIP) vs. depression (MDD) vs. control); such a method could have important clinical value, especially at disorder onset when differential diagnosis can be challenging. Here, we introduce a method, Differential Diagnosis-Polygenic Risk Score (DDx-PRS), that jointly estimates posterior probabilities of each possible diagnostic category (e.g. SCZ=50%, BIP=25%, MDD=15%, control=10%) by modeling variance/covariance structure across disorders, leveraging case-control polygenic risk scores (PRS) for each disorder (computed using existing methods) and prior clinical probabilities for each diagnostic category. DDx-PRS uses only summary-level training data and does not use tuning data, facilitating implementation in clinical settings. In simulations, DDx-PRS was well-calibrated (whereas a simpler approach that analyzes each disorder marginally was poorly calibrated), and effective in distinguishing each diagnostic category vs. the rest. We then applied DDx-PRS to Psychiatric Genomics Consortium SCZ/BIP/MDD/control data, including summary-level training data from 3 case-control GWAS ( N =41,917-173,140 cases; total N =1,048,683) and held-out test data from different cohorts with equal numbers of each diagnostic category (total N =11,460). DDx-PRS was well-calibrated and well-powered relative to these training sample sizes, attaining AUCs of 0.66 for SCZ vs. rest, 0.64 for BIP vs. rest, 0.59 for MDD vs. rest, and 0.68 for control vs. rest. DDx-PRS produced comparable results to methods that leverage tuning data, confirming that DDx-PRS is an effective method. True diagnosis probabilities in top deciles of predicted diagnosis probabilities were considerably larger than prior baseline probabilities, particularly in projections to larger training sample sizes, implying considerable potential for clinical utility under certain circumstances. In conclusion, DDx-PRS is an effective method for distinguishing clinically related disorders.

Journal Article↗

PubMed2025

Post-traumatic stress disorder and REM-sleep behavior disorder: exploring genetic associations and causal links.

OBJECTIVE: To explore potential genetic and/or causal associations between Post-Traumatic Stress Disorder and neurodegeneration-related isolated/idiopathic rapid-eye-movement sleep behavior disorder. METHODS: We conducted polygenic risk score, genetic correlation, and Mendelian randomization analyses using the latest genome-wide association studies summary statistics and individual genotyping data. Next, a blinded observer examined dopamine transporter imaging binding status-a marker of neurodegeneration-in patients with isolated/idiopathic rapid-eye movement sleep behavior disorder, with (N = 6) and without Post-Traumatic Stress Disorder (N = 32). RESULTS: Polygenic risk scores for Post-Traumatic Stress Disorder were associated with isolated/idiopathic rapid-eye-movement sleep behavior disorder, with each standard deviation increase linked to 14.7% higher odds (odds ratio = 1.15, 95% confidence interval: 1.04 to 1.26, p = 0.005). However, genetic correlation was weak, and Mendelian randomization did not support a potential causal relationship. The proportion of individuals with abnormal dopamine transporter imaging binding status was significantly higher in the Post-Traumatic Stress Disorder group compared to those without the disorder (p=0.01, X2 = 6.62). INTERPRETATION: Polygenic risk scores analysis identified an association between Post-Traumatic Stress Disorder and neurodegeneration-related isolated/idiopathic rapid-eye-movement sleep behavior disorder, consistent with the result from the small exploratory substudy. The lack of strong genetic correlation or causation may reflect limited sample size. Further research with larger and more diverse cohorts is crucial to clarify the genetic, biological and physiological mechanisms underlying this association.

Journal Article↗

PubMed2026

Large-Scale Plasma Proteomics Enhances Prediction of Liver-Related Events Among Individuals With Prediabetes and Type 2 Diabetes: A Prospective Cohort Study in the UK Biobank.

OBJECTIVE: To develop a protein risk score (ProRS) for predicting liver-related events (LREs) in patients with diabetes and compare its predictive performance with the Fibrosis-4 Index (FIB-4) and an established polygenic risk score. RESEARCH DESIGN AND METHODS: This prospective cohort study included 13 516 individuals with prediabetes and type 2 diabetes (T2D) from the UK Biobank. Cox proportional hazards models and LASSO regression were applied to identify proteins associated with incident LREs and construct the ProRS. Predictive performance was assessed using Harrell's C-index, time-dependent area under the receiver operating characteristic curve, net reclassification improvement and integrated discrimination improvement. RESULTS: Over a median follow-up of 13.5 years, 171 (1.3%) incident LREs occurred. We identified 877 proteins associated with LRE risk, primarily enriched in inflammatory signalling, extracellular matrix remodelling and complement/coagulation cascades. In the training set, we developed a 24-protein ProRS (C-index, 0.842; 95% CI 0.797-0.884) that stratified individuals into low-, medium- and high-risk groups, with 10-year cumulative incidences of LREs of 0.2%, 1.2% and 14.2%, respectively. Compared with the low-risk group, the hazard ratio for LREs was 57.1 (95% CI 31.9-102) in the high-risk group. In the internal validation set, the ProRS model (C-index, 0.876; 95% CI 0.827-0.920) accurately predicted both short- and long-term LREs and outperformed FIB-4 index (C-index, 0.733; 95% CI 0.657-0.807) and polygenic risk score (C-index, 0.636; 95% CI 0.564-0.706). CONCLUSIONS: The protein risk score demonstrated superior performance compared with the FIB-4 index and the polygenic risk score in predicting incident LREs among individuals with prediabetes and T2D. The score allows stratification of individuals according to liver-related risk, though external validation in multi-ethnic cohorts is warranted.

Humans↗

PubMed1986

Recurrence risks in an oligogenic threshold model: the effect of alterations in allele frequency.

The polygenic threshold model assumes that the distribution of the underlying liability is approximately normal. This paper examines the impact of deviations from normality in the underlying liability distribution when the number of loci affecting liability is finite, but large (e.g. 5-10). Skewness and kurtosis of the liability distribution are produced by varying the frequency of pathogenic alleles while population risk of illness is held constant by parallel changes in the threshold of manifestation. For a given population risk of illness, the recurrence risk in relatives varies widely as a function of the shape of the liability distribution. These results raise questions about the accuracy of the polygenic threshold approximation for the calculation of recurrence risks for human 'polygenic' disorders.

Alleles↗

PubMed1987

Three recessive loci required for insulin-dependent diabetes in nonobese diabetic mice.

A polygenic basis for susceptibility to insulin-dependent diabetes in nonobese diabetic (NOD) mice has been established by outcross to a related inbred strain, nonobese normal (NON). Analysis of first and second backcross progeny has shown that at least three recessive genes are required for development of overt diabetes. One, Idd-1s, is tightly linked to the H-2K locus on chromosome 17; another, Idd-2s, is localized proximal to the Thy-1/Alp-1 cluster on chromosome 9. Segregation of a third, Idd-3s, could be shown in a second backcross. Neither Idd-1s nor Idd-2s could individually be identified as the locus controlling insulitis; leukocytic infiltrates in pancreas were common in most asymptomatic BC1 mice. Both F1 and BC1 mice exhibited the unusually high percentage of splenic T lymphocytes characteristic of NOD, suggesting dominant inheritance of this trait. The polygenic control of diabetogenesis in NOD mice, in which a recessive gene linked to the major histocompatibility complex is but one of several controlling loci, suggests that similar polygenic interactions underlie this type of diabetes in humans.

Animals↗

PubMed1974

Transition of the R factor R12 in Proteus mirabilis.

When Proteus mirabilis harboring the R factor R12 (a round of replication mutant of the R factor NR1) is cultured in medium containing streptomycin there can be an amplification in the number of copies of r-determinants per cell and the formation of enlarged polygenic R factors containing repeated sequences of r-determinants as well as polygenic molecules consisting of repeated sequences of r-determinants. This phenomenon has been referred to as the "transition." When transitioned cells are then cultured in drug-free medium, within a few generations two distinct density species of R factor deoxyribonucleic acid (DNA) are observed in a CsCl density gradient: a 1.712 g/ml band of covalently closed circular R factor DNA consisting of one transfer factor (RTF-TC) plus one r-determinant and a 1.718 g/ml band consisting of repeated sequences of r-determinants. The RTF-TC component of the R factor appears to control the replication of all the R factor DNA which is attached to it. In the autonomous state, however, polygenic sequences of r-determinants do not appear to replicate under the same control mechanism as when they are attached to an RTF-TC.

Base Sequence↗

PubMed2026

Phenotypic and genotypic risk factors for uveal melanoma in a high ambient UV radiation environment.

BACKGROUND: Most evidence regarding risk factors for uveal melanoma (UM) derives from case-control studies prone to recall bias, and its rarity has limited prospective research. To address these gaps, we applied a population-based case-control design incorporating polygenic risk scores and Mendelian randomization to explore genetic and phenotypic determinants of UM risk. METHODS: The study was conducted in Queensland, Australia. Incident UM cases diagnosed between 2011 and 2022 were recruited through specialist ocular oncology clinics. Controls were participants in the QSkin Sun and Health Study, a prospective cohort of 43,794 adults aged 40-69 at baseline (2010-2011). Demographic, phenotypic, and sun exposure factors were harmonized across studies. Polygenic risk scores were calculated for pigmentation traits and nevi characteristics using genome-wide association study datasets, and Mendelian randomization was used to assess potential causal relationships with UM risk. RESULTS: Among 485 UM cases and 43,724 controls, several phenotypic traits were strongly associated with UM risk: male sex, blue or light eye color, inability to tan, freckling, and high nevus density. A family history of cutaneous melanoma and a personal history of keratinocyte cancer were also associated with higher risk. Polygenic risk score analyses confirmed significant associations for eye color and freckling. Mendelian randomization analyses supported causal relationships between lighter eye color, freckling propensity, reduced tanning ability and UM risk. CONCLUSIONS: These findings provide genetic evidence supporting a causal role for pigmentation-related traits in UM susceptibility. IMPACT: This evidence may help refine risk assessment and inform counselling for individuals with suspicious ocular lesions.

Journal Article↗

PubMed2026

Multivariate, Multi-Omic Analysis in 799,429 Individuals Identifies 134 Loci Associated with Somatoform Traits.

INTRODUCTION: Somatoform traits (e.g., health anxiety, somatic preoccupation, and bodily distress symptoms) are prevalent and pose challenges to clinical practice. Understanding their genetic basis could improve diagnostic and therapeutic approaches. METHODS: Using available summary statistics, we conducted a multivariate genome-wide association study (GWAS) and multi-omic analysis of four somatoform traits - fatigue, irritable bowel syndrome, pain intensity, and health satisfaction - in 799,429 individuals genetically similar to European reference panels. RESULTS: The GWAS identified 134 loci associated with a somatoform common factor, including 44 loci not significant in the input GWAS and 8 novel loci for somatoform traits. Novel loci were mechanistically informative, mapping to the DNM1 gene and the protocadherin gene cluster (PCDHA1-4), which are involved in nociceptor sensitization and synaptogenesis, respectively. Gene-property analyses highlighted an enrichment of genes involved in synaptic transmission and enriched expression in 11 brain tissues and the pituitary. Across two brain transcriptomic datasets, we identified 16 high-confidence genes whose expression in enriched tissues was associated with somatoform traits. There was substantial polygenic overlap (76-83%) between the somatoform and externalizing, internalizing, and general psychopathology factors. Somatoform polygenic scores were associated with obesity, type 2 diabetes, and tobacco use disorder in independent biobanks. Drug repurposing analyses suggested potential therapeutic targets, including MEK inhibitors, while Mendelian randomization analyses indicated potentially protective effects of gut microbiota. DISCUSSION: Consistent with emerging medical and genetic knowledge, somatoform traits have a shared etiology and considerable polygenic overlap with psychopathology. The biological insights from drug repurposing and Mendelian randomization analyses could provide promising avenues for treatment development.

Genetics↗

PubMed1996

Evidence for a major gene elevating serum bilirubin concentration in Utah pedigrees.

In case-control studies, lower serum bilirubin levels have been associated with increased risk of developing coronary heart disease (CHD). We have also previously shown that serum bilirubin has a significant polygenic component. The purpose of the present investigation was to determine whether there was statistical evidence for a major gene explaining a significant portion of individual variation in serum total bilirubin levels and whether this gene might alter the risk of CHD. Serum bilirubin measurements were obtained from 1240 adults in 84 Utah pedigrees screened twice: from 1980 to 1983 and again from 1983 to 1986. Bivariate maximum-likelihood segregation analysis of serum bilirubin levels obtained from the two clinic visits indicated that a major gene was responsible for elevated levels in 11.5% of the persons in these pedigrees. Phenotypic variations in visit 1 bilirubin arising from polygenes were highly correlated with the phenotypic variation due to polygenes in visit 2 bilirubin, indicating a stable genetic contribution to bilirubin over 2.5 years of follow-up. The major gene explained 27% and 28% of the variance in bilirubin levels at visit 1 and visit 2, respectively. There were no correlations of unmeasured environmental factors influencing bilirubin between the two clinic visits. At both visits, persons with early CHD had lower levels of bilirubin than unaffected persons (P < .01). The odds ratio for the risk of CHD in the high-homozygote group was 0.31, P = .09. We conclude that there is a major gene modestly raising serum bilirubin levels. Since cross-sectional data indicate that low serum bilirubin levels increase the risk of CHD, this major gene may be protective against CHD for about 12% of the persons in this study.

Adult↗

PubMed2025

Blood Pressure Genetics in Han Taiwanese With Cross-Trait Analysis in East Asians: Insights Into Comorbidities, All-Cause Mortality, and Cardiovascular Mortality.

BACKGROUND: Hypertension is a major health burden in East Asia. However, the genetic architecture and clinical implications of blood pressure (BP) traits remain underexplored beyond European-focused studies. This large-scale study aimed to investigate hypertension, systolic BP, and diastolic BP, to uncover genetic links to comorbidities and mortality in Han Taiwanese individuals. METHODS: This large-scale study used China Medical University Hospital biobank data and conducted genome-wide association studies on 25 523 hypertension cases and 47 522 controls, plus 66 236 individuals for systolic BP and 66 152 for diastolic BP. Cross-trait genetic correlations were assessed across 5 East Asian biobanks. Mendelian randomization and polygenic risk scores were applied to assess causality and predict clinical outcomes. RESULTS: We identified 8 loci and 36 genes for hypertension, 7 loci and 17 genes for systolic BP, and 9 loci and 26 genes for diastolic BP. ATP2B1 and FGF5 were common to all BP traits, implicating calcium signaling and vascular remodeling pathways. Cross-trait analyses showed shared genetic liability between BP traits and cardiovascular and metabolic comorbidities. Phenome-wide association studies confirmed strong associations with circulatory diseases. Mendelian randomization analyses demonstrated that elevated BP causally increases the risk of unstable angina pectoris. Polygenic risk scores predicted significantly higher risks and earlier onset of unstable angina pectoris, all-cause mortality, and cardiovascular mortality among individuals in the top polygenic risk score quintiles. CONCLUSIONS: Our findings highlight the genetic basis of BP and comorbidities in East Asians, suggesting that BP genetic risk may inform future approaches to early risk assessment and prevention.

Aged↗

PubMed2003

Multivariate variance-components analysis of longitudinal blood pressure measurements from the Framingham Heart Study.

Multivariate variance-components analysis provides several advantages over univariate analysis when studying correlated traits. It can test for pleiotropy or (in the longitudinal context) gene x age interaction. It can also have more power than univariate analyses to detect a quantitative trait locus influencing several traits. We apply multivariate variance components to longitudinal systolic blood pressure data from the Framingham Heart Study. We find evidence for a polygenic influence on blood pressure (heritabilities at different ages range from 27% to 38%). Tests based on a factor-analytic parameterization of the polygenic variance find significant (p < 2 x 10(-3)) evidence that different genes affect blood pressure at different ages. Still, estimates for the proportion of polygenic variance due to shared genes ran as high as 85% for some trait pairs. Univariate and multivariate linkage analyses replicate previous linkage results on chromosome 17 (maximum LOD scores of 2.2 and 2.4, respectively). In this study, multivariate analysis provides no increase in power; this is likely due to the strong positive correlation in systolic blood pressure measured at different ages.

Adult↗

PubMed2001

Genetic determinants of type 2 diabetes.

Hyperglycemia of type 2 diabetes mellitus (T2DM) results from a complex interplay of genetic and environmental factors that influence a number of intermediate traits (e.g., beta-cell mass, insulin secretion, insulin action, fat distribution, obesity). The primary biochemical events leading to diabetes are still unknown in most cases. Although several monogenic forms of diabetes have been identified, T2DM seems to be a polygenic disorder in the majority of cases. T2DM is probably also multigenic, meaning that many different combinations of gene defects may exist among diabetic patients. Significant results were obtained in the identification of the genetic determinants of monogenic forms of diabetes with young age of onset. However, despite the evidence for a strong genetic background, little of the genetic risk factors for the more-common forms of polygenic T2DM are known to date. The goal of this chapter is to summarize and discuss the significant results of recent literature on the genetics of both the monogenic and polygenic forms of T2DM.

Age of Onset↗

PubMed2003

Site and gender specificity of inheritance of bone mineral density.

UNLABELLED: Differences in genetic control of BMD by skeletal sites and genders were examined by complex segregation analysis in 816 members of 147 families with probands with extreme low BMD. Spine BMD correlated more strongly in male-male comparisons and hip BMD in female-female comparisons, consistent with gender- and site-specificity of BMD heritability. INTRODUCTION: Evidence from studies in animals and humans suggests that the genetic control of bone mineral density (BMD) may differ at different skeletal sites and between genders. This question has important implications for the design and interpretation of genetic studies of osteoporosis. METHODS: We examined the genetic profile of 147 families with 816 individuals recruited through probands with extreme low BMD (T-score < -2.5, Z-score < -2.0). Complex segregation analysis was performed using the Pedigree Analysis Package. BMD was measured by DXA at both lumbar spine (L1-L4) and femoral neck. RESULTS: Complex segregation analysis excluded purely monogenic and environmental models of segregation of lumbar spine and femoral neck BMD in these families. Pure polygenic models were excluded at the lumbar spine when menopausal status was considered as a covariate, but not at the femoral neck. Mendelian models with a residual polygenic component were not excluded. These models were consistent with the presence of a rare Mendelian genotype of prevalence 3-19%, causing high BMD at the hip and spine in these families, with additional polygenic effects. Total heritability range at the lumbar spine was 61-67% and at the femoral neck was 44-67%. Significant differences in correlation of femoral neck and lumbar spine BMD were observed between male and female relative pairs, with male-male comparisons exhibiting stronger lumbar spine BMD correlation than femoral neck, and female-female comparisons having greater femoral neck BMD correlation than lumbar spine. These findings remained true for parent-offspring correlations when menopausal status was taken into account. The recurrence risk ratio for siblings of probands of a Z-score < -2.0 was 5.4 at the lumbar spine and 5.9 at the femoral neck. CONCLUSIONS: These findings support gender- and site-specificity of the inheritance of BMD. These results should be considered in the design and interpretation of genetic studies of osteoporosis.

Bone Density↗