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Background and Purpose: Very few cases of intracranial aneurysms (IAs) in twins have been reported. Previous work has suggested that vulnerability to IA formation is heritable. Twin studies provide an opportunity to evaluate the impact of genetics on IA characteristics, including IA location. We therefore sought to examine IA location concordance, multiplicity, and rupture status within affected twin-pairs. Methods: The Familial Intracranial Aneurysm study was a multicenter study whose goal was to identify genetic and other risk factors for formation and rupture of IAs. The study required at least three affected family members or an affected sibling pair for inclusion. Subjects with fusiform aneurysms, an IA associated with an AVM, or a family history of conditions known to predispose to IA formation, such as polycystic kidney disease, Ehlers-Danlos syndrome, Marfan syndrome, fibromuscular dysplasia, or moyamoya syndrome were excluded. Twin-pairs were identified by birth date and were classified as monozygotic (MZ) or dizygotic (DZ) through DNA marker genotypes. In addition to zygosity, we evaluated twin-pairs by smoking status, major arterial territory of IAs, and rupture status. Location concordance was defined as the presence of an IA in the same arterial distribution (ICA, MCA, ACA, and vertebrobasilar), irrespective of laterality, in both members of a twin-pair. The Fisher exact test was used for comparisons between MZ and DZ twin-pairs. Results: A total of 16 affected twin-pairs were identified. Location concordance was observed in 8 of 11 MZ twin-pairs but in only 1 of 5 DZ twin-pairs (p = 0.08). Three MZ subjects had unknown IA locations and comprised the three instances of MZ discordance. Six of the 11 MZ twin-pairs and none of the 5 DZ twin-pairs had IAs in the ICA distribution (p = 0.03). Multiple IAs were observed in 11 of 22 MZ and 5 of 10 DZ twin-pairs. Thirteen (13) of the 32 subjects had an IA rupture, including 10 of 22 MZ twins. Conclusions: We found that arterial location concordance was greater in MZ than DZ twins, which suggests a genetic influence upon aneurysm location. The 16 twin-pairs in the present study are nearly the total of affected twin-pairs that have been reported in the literature to date. Further studies are needed to determine the impact of genetics in the formation and rupture of IAs.

Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency. We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants. Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1·9×10 −109 for rs2282679, in GC); 11q12 (p=2·1×10 −27 for rs12785878, near DHCR7); and 11p15 (p=3·3×10 −20 for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6·0×10 −10 for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2·47, 95% CI 2·20–2·78, p=2·3×10 −48) or lower than 50 nmol/L (1·92, 1·70–2·16, p=1·0×10 −26) compared with those in the lowest quartile. Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency. Full funding sources listed at end of paper (see Acknowledgments).

Since becoming clinically available in 2011, the use of noninvasive prenatal testing (NIPT) to screen for fetal aneuploidy has continued to increase. However, it has been questioned whether the education of patients undergoing NIPT consistently meets informed consent standards. We sought to evaluate patients’ basic understanding of NIPT, such as conditions assessed and accuracy. In addition, we investigated patient self-assessment of NIPT knowledge and satisfaction with the testing process. We distributed an anonymous paper survey to pregnant women during prenatal visits following a negative NIPT result. The survey assessed patient NIPT knowledge, gathered pregnancy-specific and demographic information, and allowed respondents to rank their basic understanding of NIPT and provide written feedback about the testing process. A total of 95 completed and 3 partially completed surveys were returned. Participants scored lowest on knowledge questions involving whether a negative NIPT result ensures a healthy baby or eliminates the possibility of Down syndrome. Most perceived themselves to have a good basic understanding of NIPT and two-thirds of the written feedback proposed no changes to NIPT administration. Overall, most patients appear satisfied with their understanding of NIPT and the testing process, yet they may not fully appreciate the limitations of this screening method.

Predictive testing for Huntington disease (HD) has been available in the United States (US) since 1987, and the Indiana University Predictive Testing Program has been providing this testing since 1990. To date there has been no published description of those who present for such testing in the US. Here we describe demographics of 141 individuals and reproductive decision making of a subset of 16 of those individuals who underwent predictive HD testing between 1990 and 2010 at one site in the US. This study is a retrospective chart review of the “Personal History Questionnaire” participants completed prior to testing. As seen in other studies, most participants were female (64.5 %), in their mid-30s (mean = 34), and had at least one child prior to testing (54 %). Multiple demographic datum points are described, and the reproductive decision making of these at-risk individuals was analyzed using Fisher’s Exact Tests. Of those women who had children before learning of their risk to inherit HD, those who attended church more frequently, had three or more children total, or whose mother was affected with HD were more likely to be comfortable with their choice to have children. We conclude that these demographic factors influence the reproductive decision-making of individuals at risk for HD. Psychologists, clinical geneticists, and genetic counselors may be able to use this information to help counsel at-risk patients regarding current or past reproductive decision making.

Finding genetic variants that contribute to phenotypic variation is one of the main challenges of modern genetics. We used an outbred population of rats (Heterogeneous Stock, HS) in a combined sequence-based and genetic mapping analysis to identify sequence variants and genes contributing to complex traits of biomedical relevance. Here we describe the sequences of the eight inbred progenitors of the HS and the variants that segregate between them. We report the genotyping of 1,407 HS rats, and the collection from 2,006 rats of 195 phenotypic measures that are relevant to models of anxiety, type 2 diabetes, hypertension and osteoporosis. We make available haplotype dosages for the 1,407 genotyped rats, since genetic mapping in the HS is best carried out by reconstructing each HS chromosome as a mosaic of the progenitor genomes. Finally, we have deposited an R object that makes it easy to incorporate our sequence data into any genetic study of HS rats. Our genetic data are available for both Rnor3.4 and Rnor5.0 rat assemblies.

Phenotypic variation in bone mineral density (BMD) among healthy adults is influenced by both genetic and environmental factors. Sequence variations in the adenylate cyclase 10 ( ADCY10 ) gene, which is also called soluble adenylate cyclase, have previously been associated with low spinal BMD in hypercalciuric patients. Since ADCY10 is located in the region linked to spinal BMD in our previous linkage analysis, we tested whether polymorphisms in this gene are also associated with normal BMD variation in healthy adults. Sixteen single-nucleotide polymorphisms (SNPs) distributed throughout ADCY10 were genotyped in two healthy groups of American whites: 1692 premenopausal women and 715 men. Statistical analyses were performed in the two groups to test for association between these SNPs and the femoral neck and lumbar spine areal BMD. We observed significant evidence of association ( p  < 0.01), with one SNP each in men and women. Genotypes at these SNPs accounted for <1% of hip BMD variation in men but 1.5% of spinal BMD in women. However, adjacent SNPs did not corroborate the association in either men or women. In conclusion, we found a modest association between an ADCY10 polymorphism and the spinal areal BMD in premenopausal white women.

Previously, we identified the regions of chromosomes 10q12-q31 and 15p16-q21 harbor quantitative trait loci (QTLs) for lumbar volumetric bone mineral density (vBMD) in female F2 rats derived from Fischer 344 (F344) × Lewis (LEW) and Copenhagen 2331 (COP) × Dark Agouti (DA) crosses. The purpose of this study is to identify the candidate genes within these QTL regions contributing to the variation in lumbar vBMD. RNA was extracted from bone tissue of F344, LEW, COP, and DA rats. Microarray analysis was performed using Affymetrix Rat Genome 230 2.0 Arrays. Genes differentially expressed among the rat strains were then ranked based on the strength of the correlation with lumbar vBMD in F2 animals derived from these rats. Quantitative PCR (qPCR) analysis was performed to confirm the prioritized candidate genes. A total of 285 genes were differentially expressed among all strains of rats with a false discovery rate less than 10%. Among these genes, 18 candidate genes were prioritized based on their strong correlation (r ² > 0.90) with lumbar vBMD. Of these, 14 genes (Akap1, Asgr2, Esd, Fam101b, Irf1, Lcp1, Ltc4s, Mdp-1, Pdhb, Plxdc1, Rabep1, Rhot1, Slc2a4, Xpo4) were confirmed by qPCR. We identified several novel candidate genes influencing spinal vBMD in rats.

The variation in several of the risk factors for osteoporotic fracture, including bone mineral density (BMD), has been shown to be strongly influenced by genetic differences. However, the genetic architecture of BMD is complex in both humans and in model organisms. We previously reported quantitative trait locus (QTL) results for BMD from a genome screen of 828 F2 progeny of Copenhagen and dark agouti rats. These progeny also provide an excellent opportunity to search for epistatic effects, or interaction between genetic loci, that contribute to fracture risk. Microsatellite marker data from a 20-cM genome screen was analyzed along with weight-adjusted bone density (DXA and pQCT) phenotypic data using the R/qtl software package. Genotype and phenotype data were permuted to determine genome-wide significance thresholds for the full model and epistasis (interaction) LOD scores corresponding to an alpha level of 0.01. A novel locus on chromosome 15 and a previously reported chromosome 14 QTL demonstrated a strong epistatic effect on BMD at the femur by DXA (LOD = 5.4). Two novel QTLs on chromosomes 2 and 12 were found to interact to affect total BMD at the femur midshaft by pQCT (LOD = 5.0). These results provide new information regarding the mode of action of previously identified QTL in the rat, as well as identifying novel loci that act in combination with known QTL or with other novel loci to contribute to BMD variation.

Peak bone mineral density (BMD) achieved during adulthood is a major determinant of osteoporotic fracture in later life. Although environmental factors affect peak BMD, it is a highly heritable trait. Recently, bone morphogenetic protein 2 (BMP2) was reported as a susceptibility gene for osteoporotic fractures and low BMD in Icelandic and Danish populations. To determine whether polymorphisms in the BMP2 gene contribute to BMD variation in our population of healthy American whites, we tested seven single nucleotide polymorphisms (SNPs), four of which were associated with osteoporotic phenotypes in the previous study. BMD at the femoral neck and lumbar spine (L2-L4) were measured by dual energy X-ray absorptiometry (DXA) in 411 men (age 18-61) and 1,291 pre-menopausal women (age 20-50). SNP genotypes/haplotypes were tested for population-based association with BMD using analysis of variance. None of the polymorphisms tested reached statistical significance (all p values >0.05) for BMD at the femoral neck or lumbar spine in either gender. Two of the SNP haplotypes spanning the entire BMP2 gene were marginally associated with BMD in men (p values=0.019-0.043). However, these haplotypes would account for only a small, if any, portion of BMD variation and would not be significant after adjustment for multiple comparisons. These results demonstrate that genetic variations in BMP2 do not substantially contribute to BMD variation in our population of healthy American whites.

Heritability of bone mineral density (BMD) varies across skeletal sites, reflecting different relative contributions of genetic and environmental influences. To quantify the degree to which common genetic variants tag and environmental factors influence BMD, at different sites, we estimated the genetic (rg) and residual (re) correlations between BMD measured at the upper limbs (UL-BMD), lower limbs (LL-BMD) and skull (SK-BMD), using total-body DXA scans of ∼ 4,890 participants recruited by the Avon Longitudinal Study of Parents and their Children (ALSPAC). Point estimates of rg indicated that appendicular sites have a greater proportion of shared genetic architecture (LL-/UL-BMD rg = 0.78) between them, than with the skull (UL-/SK-BMD rg = 0.58 and LL-/SK-BMD rg = 0.43). Likewise, the residual correlation between BMD at appendicular sites (r(e) = 0.55) was higher than the residual correlation between SK-BMD and BMD at appendicular sites (r(e) = 0.20-0.24). To explore the basis for the observed differences in rg and re, genome-wide association meta-analyses were performed (n ∼ 9,395), combining data from ALSPAC and the Generation R Study identifying 15 independent signals from 13 loci associated at genome-wide significant level across different skeletal regions. Results suggested that previously identified BMD-associated variants may exert site-specific effects (i.e. differ in the strength of their association and magnitude of effect across different skeletal sites). In particular, variants at CPED1 exerted a larger influence on SK-BMD and UL-BMD when compared to LL-BMD (P = 2.01 × 10(-37)), whilst variants at WNT16 influenced UL-BMD to a greater degree when compared to SK- and LL-BMD (P = 2.31 × 10(-14)). In addition, we report a novel association between RIN3 (previously associated with Paget's disease) and LL-BMD (rs754388: β = 0.13, SE = 0.02, P = 1.4 × 10(-10)). Our results suggest that BMD at different skeletal sites is under a mixture of shared and specific genetic and environmental influences. Allowing for these differences by performing genome-wide association at different skeletal sites may help uncover new genetic influences on BMD.