Extensive epidemiologic studies have suggested that adult disease risk is associated with adverse environmental conditions early in development. Although the mechanisms behind these relationships are unclear, an involvement of epigenetic dysregulation has been hypothesized. Here we show that individuals who were prenatally exposed to famine during the Dutch Hunger Winter in 1944 -45 had, 6 decades later, less DNA methylation of the imprinted IGF2 gene compared with their unexposed, same-sex siblings. The association was specific for periconceptional exposure, reinforcing that very early mammalian development is a crucial period for establishing and maintaining epigenetic marks. These data are the first to contribute empirical support for the hypothesis that early-life environmental conditions can cause epigenetic changes in humans that persist throughout life.developmental origins ͉ DNA methylation ͉ insulin-like growth factor II ͉ nutrition ͉ periconception S uperimposed on the DNA sequence is a layer of epigenetic information that is heritable, particularly during mitosis, and controls the potential of a genomic region to be transcribed (1). Methyl groups coupled to cytosines in cytosine-guanine (CpG) dinucleotides and modifications of histones that package the DNA are the two main molecular marks that compose this information and regulate chromatin structure and DNA accessibility (2).Animal studies have indicated that certain transient environmental influences can produce persistent changes in epigenetic marks that have life-long phenotypic consequences (3, 4). Early embryonic development is of special interest in this respect, because this is a crucial period for establishing and maintaining epigenetic marks (5). Indeed, culturing of preimplantation mice embryos found that epigenetic marks are susceptible to nutritional conditions in the very early stages of mammalian development (6, 7). One of the rare opportunities for studying the relevance of such findings to humans is presented by individuals who were prenatally exposed to famine during the Dutch Hunger Winter (8). This period of famine was the consequence of a Germanimposed food embargo in the western part of The Netherlands toward the end of World War II in the winter of 1944-45. During this period, registries and health care remained intact, so that individuals who were prenatally exposed to this famine can be traced. Moreover, the period of famine was clearly defined, and official food rations were documented. These unique features allow us to assess whether prenatal exposure to famine is associated with persistent epigenetic differences in humans.One of the best-characterized epigenetically regulated loci is insulin-like growth factor II (IGF2). IGF2 is a key factor in human growth and development and is maternally imprinted (9). Imprinting is maintained through the IGF2 differentially methylated region (DMR), the hypomethylation of which leads to bi-allelic expression of IGF2 (10). We recently studied IGF2 DMR methylation in 372 twins (11). IGF2 D...

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explain one-fifth of heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ~2,000, ~3,700 and ~9,500 SNPs explained ~21%, ~24% and ~29% of phenotypic variance. Furthermore, all common variants together captured the majority (60%) of heritability. The 697 variants clustered in 423 loci enriched for genes, pathways, and tissue-types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin, and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

Bone mineral density (BMD) is the most important predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and East Asian ancestry. We tested the top-associated BMD markers for replication in 50,933 independent subjects and for risk of low-trauma fracture in 31,016 cases and 102,444 controls. We identified 56 loci (32 novel)associated with BMD atgenome-wide significant level (P<5×10−8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal-stem-cell differentiation, endochondral ossification and the Wnt signalling pathways. However, we also discovered loci containing genes not known to play a role in bone biology. Fourteen BMD loci were also associated with fracture risk (P<5×10−4, Bonferroni corrected), of which six reached P<5×10−8 including: 18p11.21 (C18orf19), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1%, a large increase in the number of SNPs tested in association studies and can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.

Inter-individual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. Here, in a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in a further 10,739 individuals, we identified seven loci, including five novel loci, associated with mean LTL (P<5x10−8). Five of the loci contain genes (TERC, TERT, NAF1, OBFC1, RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all seven loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of CAD (21% (95% CI: 5–35%) per standard deviation in LTL, p=0.014). Our findings support a causal role of telomere length variation in some age-related diseases.