Medical genetics was revolutionized during the 1980s by the application of genetic mapping to locate the genes responsible for simple Mendelian diseases. Most diseases and traits, however, do not follow simple inheritance patterns. Genetics have thus begun taking up the even greater challenge of the genetic dissection of complex traits. Four major approaches have been developed: linkage analysis, allele-sharing methods, association studies, and polygenic analysis of experimental crosses. This article synthesizes the current state of the genetic dissection of complex traits--describing the methods, limitations, and recent applications to biological problems.

https://focus.psychiatryonline.org/doi/pdf/10.1176/foc.4.3.442

Genetic dissection of complex traits

Medical genetics was revolutionized during the 1980s by the application of genetic mapping to locate the genes responsible for simple Mendelian diseases. Most diseases and traits, however, do not follow simple inheritance patterns. Geneticists have thus begun taking up the even greater challenge of the genetic dissection of complex traits. Four major approaches have been developed: linkage analysis, allele-sharing methods, association studies, and polygenic analysis of experimental crosses. This article synthesizes the current state of the genetic dissection of complex traits—describing the methods, limitations, and recent applications to biological problems.

Genetic Dissection of Complex Traits

IN THE DECADE SINCE THE VITAMIN D RECEPTOR (VDR) was cloned and recognized as a member of the superfamily of nuclear receptors that regulate gene expression in a ligand-dependent manner, the central role of VDR in the biology of vitamin D action has been illuminated and is being defined at the molecular level. Following renal production as the hormonal metabolite of vitamin D, 1a,25-dihydroxyvitamin D3 (1,25(OH)2D3) functions as the ligand for VDR, with the hormone–receptor complex inducing calcemic and phosphatemic effects that result in normal bone mineralization and remodeling. VDR not only mediates the action of 1,25(OH)2D3 in calcium/phosphate translocating tissues, primarily intestine, but also elicits a myriad of apparent bioactivities in other major cell systems in the organism, including immune, neural, epithelial, and endocrine. The scope of this review will be limited to highlighting the actions of 1,25(OH)2D3 mediated by nuclear VDR and discussing new developments in the structure/function analysis of the receptor, including the phenotype of VDR knockout mice and the biochemical classification of patients with point mutations in the receptor. These new advances, along with other recent research, will be interpreted to update our understanding of the molecular role of VDR, ranging from characterization of its natural gene and clinically significant polymorphisms, through its DNA contact sites and protein partners, to novel ligand analogs that hold the promise of influencing VDR conformation in a therapeutically beneficial fashion. VDR BIOLOGY

/pdf/the-nuclear-vitamin-d-receptor-biological-and-molecular-41a27f8wag.pdf

The nuclear vitamin D receptor: biological and molecular regulatory properties revealed.

https://repub.eur.nl/pub/73442/1-s2.0-S0378111904003075-main.pdf

Genetics and biology of vitamin D receptor polymorphisms.

1 alpha,25-Dihydroxyvitamin D3[1 alpha,25(OH)2D3], an active form of vitamin D, has roles in many biological phenomena such as calcium homeostasis and bone formation, which are thought to be mediated by the 1 alpha,25(OH)2D3 receptor (VDR), a member of the nuclear hormone receptor superfamily. However, the molecular basis for the actions of 1 alpha,25(OH)2D3 in bone formation, its role during development and VDR genetic polymorphisms for predicting bone mineral density are uncertain. To investigate the functional role of VDR, we generated mice deficient in VDR by gene targeting. We report here that in VDR null mutant mice, no defects in development and growth were observed before weaning, irrespective of reduced expression of vitamin D target genes. After weaning, however, mutants failed to thrive, with appearance of alopoecia, hypocalcaemia and infertility, and bone formation was severely impaired as a typical feature of vitamin D-dependent rickets type II (refs 8, 9). Unlike humans with this disease, most of the null mutant mice died within 15 weeks after birth, and uterine hypoplasia with impaired folliculogenesis was found in female reproductive organs. These defects, such as alopoecia and uterine hypoplasia, were not observed in vitamin D-deficient animals. The findings establish a critical role for VDR in growth, bone formation and female reproduction in the post-weaning stage.

Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning

Bone density achieved in early adulthood is the major determinant of risk of osteoporotic fracture. Up to 60% of women suffer osteoporotic fractures as a result of low bone density, which is under strong genetic control acting through effects on bone turnover. Here we show that common allelic variants in the gene encoding the vitamin D receptor can be used to predict differences in bone density, accounting for up to 75% of the total genetic effect on bone density in healthy individuals. The genotype associated with lower bone density was overrepresented in postmenopausal women with bone densities more than 2 standard deviations below values in young normal women. The molecular mechanisms by which bone density is regulated by the vitamin D receptor gene are not certain, although allelic differences in the 3' untranslated region may alter messenger RNA levels. These findings could open new avenues to the development and targeting of prophylactic interventions. It follows that other pathophysiological processes considered to be subject to complex multifactorial genetic regulation may also be modulated by a single gene with pleiotropic transcriptional actions.

Prediction of Bone-Density from Vitamin-D Receptor Alleles

Prediction of Bone Density from Vitamin D Receptor Alleles

Nature 367, 284-287 (1994) .... In order to expand our original observations of a relationship between bone density and vitamin D receptor (VDR) genotype and to examine other genes potentially involved in bone biology, we set out to recruit a larger set of identical and non-identical twins. On re-analysis of these newly collected and re-genotyped samples, we found reduced correlation of the VDR genotype with bone density in this larger sample of twin pairs.

/pdf/correction-prediction-of-bone-density-from-vitamin-d-5by74c463y.pdf

Correction: Prediction of bone density from vitamin D raceptor alleles

Osteoporosis with its significant mortality and disability is an increasing health care problem in all aging societies. One of the major reasons for growing health care interest in osteoporosis is aging occurring in the populations of most Western societies. Indeed, while the population is aging, disability including that associated with osteoporosis is occurring at the same or relatively younger ages. Hence, the total burden and the overall proportion of health care costs expended on the elderly is increasing. Although osteoporotic fractures, and even hip fractures, are considered to be a problem largely limited to women, men are at risk, and with further aging this problem is increasing. From our Dubbo Osteoporosis Epidemiology Study [1], we have estimated remaining lifetime risk of a fracture at 60 years of age is 50-60% for a woman and 25-30% for a man. There is now clear evidence from prospective studies that low bone density (osteoporosis) is a necessary if not sufficient condition for an osteoporotic fracture. Our research has focused on the development of peak bone density, which is the major determinant of bone density in women for at least 15 years after the menopause and presumably much later in life for men. Although life-style and environmental factors playa role in the achievement of peak bone density, genetic factors appear to be more important. It is critical, however, to distinguish in terms of genetics the concept of a gross aberration associated with a gene mutation, which can result in serious physiological problems if not death, and normal \"allelic variations,\" which may be associated with little discernible biological effects. In the area of osteoporosis, osteogenesis imperfecta represents one of many mutations that lead to gross disturbance of bone function. On the other hand, the great majority of subjects with osteoporosis seem to be just a part of the normal range of bone density for age. It is this great majority that has been the target of our studies of the genetic effects on bone density development and maintenance. The model we and others have used is that of twins [2-6]. In monozygotic (MZ) twins, all genes are the same and any differences in a parameter, e.g., bone density, must be due to environmental or life-style differences or simple measurement error. On the other hand, in dizygotic (DZ) twins, on average only half the genes are shared, so any difference in bone density could be due to the superimposition of a genetic effect. In the lumbar spine and to a lesser extent femoral neck and forearm, the bone density of MZ twins is much more similar than in DZ twins, consistent with a strong genetic effect, perhaps explaining 75-80% of the variation in bone density in the population.

Jian Cheng Qi

Papers

Prediction of Bone-Density from Vitamin-D Receptor Alleles

Prediction of Bone Density from Vitamin D Receptor Alleles

Correction: Prediction of bone density from vitamin D raceptor alleles

Genetics of Osteoporosis and Vitamin D Receptor Alleles