A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance

Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.     

Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease

Several risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further, we combined data from three studies on Crohn's disease (a total of 3,230 cases and 4,829 controls) and carried out replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 additional loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1 and ITLN1. The expanded molecular understanding of the basis of this disease offers promise for informed therapeutic development.     

Common sequence variants on 20q11.22 confer melanoma susceptibility

We conducted a genome-wide association pooling study for cutaneous melanoma and performed validation in samples totaling 2,019 cases and 2,105 controls. Using pooling, we identified a new melanoma risk locus on chromosome 20 (rs910873 and rs1885120), with replication in two further samples (combined P < 1 x 10(-15)). The per allele odds ratio was 1.75 (1.53, 2.01), with evidence for stronger association in early-onset cases.     

Closing gaps in the human genome with fosmid resources generated from multiple individuals

The human genome sequence has been finished to very high standards; however, more than 340 gaps remained when the finished genome was published by the International Human Genome Sequencing Consortium in 2004. Using fosmid resources generated from multiple individuals, we targeted gaps in the euchromatic part of the human genome. Here we report 2,488,842 bp of previously unknown euchromatic sequence, 363,114 bp of which close 26 of 250 euchromatic gaps, or 10%, including two remaining euchromatic gaps on chromosome 19. Eight (30.7%) of the closed gaps were found to be polymorphic. These sequences allow complete annotation of several human genes as well as the assignment of mRNAs. The gap sequences are 2.3-fold enriched in segmentally duplicated sequences compared to the whole genome. Our analysis confirms that not all gaps within 'finished' genomes are recalcitrant to subcloning and suggests that the paired-end-sequenced fosmid libraries could prove to be a rich resource for completion of the human euchromatic genome.     

Newly identified loci that influence lipid concentrations and risk of coronary artery disease

To identify genetic variants influencing plasma lipid concentrations, we first used genotype imputation and meta-analysis to combine three genome-wide scans totaling 8,816 individuals and comprising 6,068 individuals specific to our study (1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables) and 2,758 individuals from the Diabetes Genetics Initiative, reported in a companion study in this issue. We subsequently examined promising signals in 11,569 additional individuals. Overall, we identify strongly associated variants in eleven loci previously implicated in lipid metabolism (ABCA1, the APOA5-APOA4-APOC3-APOA1 and APOE-APOC clusters, APOB, CETP, GCKR, LDLR, LPL, LIPC, LIPG and PCSK9) and also in several newly identified loci (near MVK-MMAB and GALNT2, with variants primarily associated with high-density lipoprotein (HDL) cholesterol; near SORT1, with variants primarily associated with low-density lipoprotein (LDL) cholesterol; near TRIB1, MLXIPL and ANGPTL3, with variants primarily associated with triglycerides; and a locus encompassing several genes near NCAN, with variants strongly associated with both triglycerides and LDL cholesterol). Notably, the 11 independent variants associated with increased LDL cholesterol concentrations in our study also showed increased frequency in a sample of coronary artery disease cases versus controls.     

Identification of ten loci associated with height highlights new biological pathways in human growth

Height is a classic polygenic trait, reflecting the combined influence of multiple as-yet-undiscovered genetic factors. We carried out a meta-analysis of genome-wide association study data of height from 15,821 individuals at 2.2 million SNPs, and followed up the strongest findings in >10,000 subjects. Ten newly identified and two previously reported loci were strongly associated with variation in height (P values from 4 x 10(-7) to 8 x 10(-22)). Together, these 12 loci account for approximately 2% of the population variation in height. Individuals with < or =8 height-increasing alleles and > or =16 height-increasing alleles differ in height by approximately 3.5 cm. The newly identified loci, along with several additional loci with strongly suggestive associations, encompass both strong biological candidates and unexpected genes, and highlight several pathways (let-7 targets, chromatin remodeling proteins and Hedgehog signaling) as important regulators of human stature. These results expand the picture of the biological regulation of human height and of the genetic architecture of this classical complex trait.     

ADAMTS5 is the major aggrecanase in mouse cartilage in vivo and in vitro

Aggrecan is the major proteoglycan in cartilage, endowing this tissue with the unique capacity to bear load and resist compression. In arthritic cartilage, aggrecan is degraded by one or more 'aggrecanases' from the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family of proteinases. ADAMTS1, 8 and 9 have weak aggrecan-degrading activity. However, they are not thought to be the primary aggrecanases because ADAMTS1 null mice are not protected from experimental arthritis, and cleavage by ADAMTS8 and 9 is highly inefficient. Although ADAMTS4 and 5 are expressed in joint tissues, and are known to be efficient aggrecanases in vitro, the exact contribution of these two enzymes to cartilage pathology is unknown. Here we show that ADAMTS5 is the major aggrecanase in mouse cartilage, both in vitro and in a mouse model of inflammatory arthritis. Our data suggest that ADAMTS5 may be a suitable target for the development of new drugs designed to inhibit cartilage destruction in arthritis, although further work will be required to determine whether ADAMTS5 is also the major aggrecanase in human arthritis.     

The DNA sequence of the human X chromosome

The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence.