Type 1 diabetes (T1D) is a common autoimmune disorder that arises from the action of multiple genetic and environmental risk factors. We report the findings of a new genome-wide association study of T1D, combined in a meta-analysis with two previously published studies. The total sample set included 7,514 cases and 9,045 reference samples. Forty-one distinct genomic locations provided evidence for association to T1D in the meta-analysis (P < 10-6). After excluding previously reported associations, 27 regions were further tested in an independent set of 4,267 cases, 4,463 controls and 2,319 affected sib-pair (ASP) families. Of these, 18 regions were replicated (P < 0.01; overall P < 5 × 10-8) and four additional regions provided nominal evidence of replication (P < 0.05). The many new candidate genes suggested by these results include IL10, IL19, IL20, GLIS3, CD69 and IL27.

The increasing number of DNA polymorphisms characterized in humans will soon allow the construction of fine genetic maps of human chromosomes. This advance calls for a reexamination of current methodologies for linkage analysis by the family method. We Just as molecular hybridization has given a new power to methods for physical assignments (1), the new wealth of DNA polymorphisms (2, 3) will elicit the development of new strategies for linkage analysis by family methods. When only about 30 genetic markers were available at arbitrary locations, affording a very partial coverage of the human genome, a natural approach for the detection of linkage between a disease locus and a battery of markers consisted in the pairwise analysis of the disease phenotype and each marker in turn. Two-locus linkage analysis by the now classical method of lod-scores (4) or related techniques was originally restricted to simple Mendelian traits and nuclear families; later it was extended to complex phenotypes and general pedigrees through the development of appropriate algorithms and computer programs (5-7).More than 200 DNA polymorphisms have been defined in recent years (8), and there is no doubt that the number required to span the human genome (2, 9) will be reached soon.This inevitably raises questions regarding the relative merits of two-point and multipoint linkage analysis. Although the advantages of multipoint tests, as opposed to pairwise tests, seems generally intuitive (10), a systematic investigation is necessary before new approaches can be proposed.Need for a multilocus analysis is evident for the calculation of genetic risks when several linked markers are available; otherwise there would be no general way of combining pedigree calculations involving each marker singly. For detection of linkage, estimation of recombination, and construction of genetic maps, the merit of multipoint tests has yet to be established. Although Meyers et al. (11) considered three-point tests in restricted situations, most procedures for estimation of recombination and genetic mapping in humans have been based on the assumption that results from independent two-point linkage tests are combined (12)(13)(14).The determination of a genetic map from results of linkage analyses requires assumptions about the mathematical relationships between map distance, expressed in units of crossing-over, or morgans, and recombination frequency, thus defining a mapping function. This relation is complex because recombination results from an odd number of points of exchange between loci, and evidence points to their nonindependence-i.e., interference in crossing-over (15). Various mapping functions have been proposed embodying specific assumptions regarding interference (15). Statistical methods have been proposed that assume a mapping function or a specific process of chiasma formation (12)(13)(14) or that infer a genetic map solely from the rank-order constraints implied by pairwise recombination estimates (16).As the genetic map is developed, it is...

Wolcott-Rallison syndrome (WRS) is a rare, autosomal recessive disorder characterized by permanent neonatal or early infancy insulin-dependent diabetes. Epiphyseal dysplasia, osteoporosis and growth retardation occur at a later age. Other frequent multisystemic manifestations include hepatic and renal dysfunction, mental retardation and cardiovascular abnormalities. On the basis of two consanguineous families, we mapped WRS to a region of less than 3 cM on chromosome 2p12, with maximal evidence of linkage and homozygosity at 4 microsatellite markers within an interval of approximately 1 cM. The gene encoding the eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3) resides in this interval; thus we explored it as a candidate. We identified distinct mutations of EIF2AK3 that segregated with the disorder in each of the families. The first mutation produces a truncated protein in which the entire catalytic domain is missing. The other changes an amino acid, located in the catalytic domain of the protein, that is highly conserved among kinases from the same subfamily. Our results provide evidence for the role of EIF2AK3 in WRS. The identification of this gene may provide insight into the understanding of the more common forms of diabetes and other pathologic manifestations of WRS.