The vitamin D endocrine system is involved in a wide variety of biological processes including bone metabolism, modulation of the immune response, and regulation of cell proliferation and differentiation. Variations in this endocrine system have, thus, been linked to several common diseases, including osteoarthritis (OA), diabetes, cancer, cardiovascular disease, and tuberculosis. Evidence to support this pleiotropic character of vitamin D has included epidemiological studies on circulating vitamin D hormone levels, but also genetic epidemiological studies. Genetic studies provide excellent opportunities to link molecular insights with epidemiological data and have therefore gained much interest. DNA sequence variations, which occur frequently in the population, are referred to as "polymorphisms" and can have modest and subtle but true biological effects. Their abundance in the human genome as well as their high frequencies in the human population have made them targets to explain variation in risk of common diseases. Recent studies have indicated many polymorphisms to exist in the vitamin D receptor (VDR) gene, but the influence of VDR gene polymorphisms on VDR protein function and signaling is largely unknown. So far, three adjacent restriction fragment length polymorphisms for BsmI, ApaI, and TaqI, respectively, at the 3' end of the VDR gene have been the most frequently studied. Because these polymorphisms are probably nonfunctional, linkage disequilibrium with one or more truly functional polymorphisms elsewhere in the VDR gene is assumed to explain the associations observed. Research is therefore focussed on documenting additional polymorphisms across the VDR gene to verify this hypothesis and on trying to understand the functional consequences of the variations. Substantial progress has been made that will deepen our understanding of variability in the vitamin D endocrine system and might find applications in risk assessment of disease and in predicting response-to-treatment.

Polymorphisms of the vitamin D receptor gene (VDR) have been shown to be associated with several complex diseases, including osteoporosis, but the mechanisms are unknown and study results have been inconsistent. We therefore determined sequence variation across the major relevant parts of VDR, including construction of linkage disequilibrium blocks and identification of haplotype alleles. We analyzed 15 haplotype-tagging SNPs in relation to 937 clinical fractures recorded in 6,148 elderly whites over a follow-up period of 7.4 years. Haplotype alleles of the 5' 1a/1e, 1b promoter region and of the 3' untranslated region (UTR) were strongly associated with increased fracture risk. For the 16% of subjects who had risk genotypes at both regions, their risk increased 48% for clinical fractures (P = .0002), independent of age, sex, height, weight, and bone mineral density. The population-attributable risk varied between 1% and 12% for each block and was 4% for the combined VDR risk genotypes. Functional analysis of the variants demonstrated 53% lower expression of a reporter construct with the 1e/1a promoter risk haplotype (P = 5 x 10(-7)) in two cell lines and 15% lower mRNA level of VDR expression constructs carrying 3'-UTR risk haplotype 1 in five cell lines (P = 2 x 10(-6)). In a further analysis, we showed 30% increased mRNA decay in an osteoblast cell line for the construct carrying the 3'-UTR risk haplotype (P = .02). This comprehensive candidate-gene analysis demonstrates that the risk allele of multiple VDR polymorphisms results in lower VDR mRNA levels. This could impact the vitamin D signaling efficiency and might contribute to the increased fracture risk we observed for these risk haplotype alleles.

The COLIA1 polymorphism is associated with reduced bone density and predisposes women to osteoporotic fractures.

Autistic disorder (OMIM 209850) is a disease with a significant genetic component of a complex nature. 1 Cytogenetic abnormalities in the Prader-Willi/Angelman syndrome critical region (15q11-13) have been described in several individuals with autism. 1 For this reason, markers across this region have been screened for evidence of linkage and association, and a marker (155CA-2) in the ␥-aminobutyric acid type-A receptor ␤3 subunit gene (GABRB3) has been associated in one study 2 but not others. [3][4][5] We completed an association analysis with 155CA-2 using the transmission disequilibrium test (TDT) in a set of 80 autism families (59 multiplex and 21 trios). We also used four additional markers (69CA, 155CA-1, 85CA, and A55CA-1) localized within 150 kb of 155CA-2. The use of multi-allelic TDT (MTDT) (P < 0.002), as well as the TDT (P < 0.004), demonstrated an association between autistic disorder and 155CA-2 in these families. Meiotic segregation distortion could be excluded as a possible cause for these results since no disequilibrium was observed in unaffected siblings. These findings support a role for genetic variants within the GABA receptor gene complex in 15q11-13 in autistic disorder. Molecular Psychiatry ( Autism is a development disorder characterized by impairments in three domains: communication, reciprocal social interactions, and repetitive or stereotyped behaviors and interests (for review see TagerFlusberg et al 1 ). The concordance rate for monozygotic twins is much higher than that of dizygotic twins, which indicates that genetic factors play an important role in the etiology of autism. In addition, family studies indicate that the recurrence risk to siblings, estimated from multiple studies at 1-3%, is profoundly higher than the risk to the general population, which has been estimated at ෂ0.5-2 per 1000. The mode of inheritance of autism appears to be complex; latentclass analyses suggest that 3-10 genes may underlie the disorder, 6 although an interpretation of at least one genome-wide linkage analysis has argued for Ͼ10 genes underlying the disorder. 7 Cytogenetic studies have demonstrated that duplications within the 15q11-q13 region can be associated with autism (for review see Tager-Flusberg et al 1 ). Moreover, symptoms of autism can be associated with both Prader-Willi and Angelman syndromes, both of which involve alterations in the 15q11-q13 region. Because of this, the15q11-q13 region has been examined for genetic linkage to autism. A mapping of nine markers spanning a region of ෂ2 Mb within this region in 132 families demonstrated linkage disequilibrium at a marker within the GABRB3 gene, 155CA-2. 2 An additional locus within GABRB3 that is ෂ150 kb away from 155CA-2 (D15S97) did not demonstrate linkage disequilibrium.A genome-wide scan involving 51 autistic multiplex families demonstrated a broad peak with a LOD score of about 1 over the GABRB3 region. 8 Similarly, multipoint analyses over the region in 63 families demonstrated a peak Z-score of 1.78 in the region, near the marker ...