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Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.

We propose TetraHer, a method for estimating the liability heritability of binary phenotypes. TetraHer has five key features. First, it can be applied to data from complex pedigrees that contain multiple types of relationships. Second, it can correct for ascertainment of cases or controls. Third, it can accommodate covariates. Fourth, it can model the contribution of common environment. Fifth, it produces a likelihood that can be used for significance testing. We first demonstrate the validity of TetraHer on simulated data. We then use TetraHer to estimate liability heritability for 229 codes from the tenth International Classification of Diseases (ICD-10). We identify 107 codes with significant heritability (p < 0.05/229), which can be used in future analyses for investigating the genetic architecture of human diseases. TetraHer is a new method for estimating the heritability of diseases that allows for ascertainment of cases and for contributions of covariates. Applied to UK Biobank data, TetraHer finds 107 ICD-10 codes with significant heritability. [ABSTRACT FROM AUTHOR]

Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.

A genome-wide association approach to study 1507 children from the Avon Longitudinal Study of Parents and Children (ALSPAC) was applied to identify genetic determinants underlying variation in 2D:4D. The results demonstrated that a variant within the LIN28B gene is associated with 2D:4D and is significant for the early development of the hands and is also associated with height and age at menarche.

A study uses a novel method called functional gene group analysis to test the effect of groups of genes, which are defined according to their cellular function, on cognitive ability. The analysis reveals that synaptic heterotrimeric guanine nucleotide binding proteins (G proteins) play a key role in cognitive ability, thereby offering fresh insights into the genetic basis of cognitive ability.

A study identifies genetic predictors of lymphocyte levels, which are hypothesized to be associated with immune-related diseases, and tests several variants of CD4+ T cells, CD8+ T cells, CD56+ natural killer (NK) cells and the derived CD4:CD8 ratio associated with five lymphocyte subsets. It identifies two major independent quantitative trait loci (QTL) for CD4:CD8 lymphocyte ratio, wherein CD4 and CD8 are associated with risk of type-1 diabetes and HIV-1 immune control, respectively.

A whole-genome association study is conducted for the identification of several different quantitative trait loci (QTL) that are shown to be involved with the hematology traits. The monocyte counts and erythrocyte volume are shown to be highly dependent on the sequence variants observed in these loci.

Craniofacial morphology is highly heritable, but little is known about which genetic variants influence normal facial variation in the general population. We aimed to identify genetic variants associated with normal facial variation in a population-based cohort of 15-year-olds from the Avon Longitudinal Study of Parents and Children. 3D high-resolution images were obtained with two laser scanners, these were merged and aligned, and 22 landmarks were identified and their x, y, and z coordinates used to generate 54 3D distances reflecting facial features. 14 principal components (PCs) were also generated from the landmark locations. We carried out genome-wide association analyses of these distances and PCs in 2,185 adolescents and attempted to replicate any significant associations in a further 1,622 participants. In the discovery analysis no associations were observed with the PCs, but we identified four associations with the distances, and one of these, the association between rs7559271 in PAX3 and the nasion to midendocanthion distance (n-men), was replicated (p = 4 × 10−7). In a combined analysis, each G allele of rs7559271 was associated with an increase in n-men distance of 0.39 mm (p = 4 × 10−16), explaining 1.3% of the variance. Independent associations were observed in both the z (nasion prominence) and y (nasion height) dimensions (p = 9 × 10−9 and p = 9 × 10−10, respectively), suggesting that the locus primarily influences growth in the yz plane. Rare variants in PAX3 are known to cause Waardenburg syndrome, which involves deafness, pigmentary abnormalities, and facial characteristics including a broad nasal bridge. Our findings show that common variants within this gene also influence normal craniofacial development. [ABSTRACT FROM AUTHOR]

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10 -8 ). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences., (Copyright © 2018 American Society of Human Genetics. All rights reserved.)