Volume 40 Issue 9, September 2008

Recent successes in identifying loci involved in predisposition to type 2 diabetes have been driven by genome-wide association studies in populations of European descent. A new discovery, using samples of East Asian origin, of diabetes susceptibility variants mapping to the KCNQ1 gene highlights the importance of extending these studies to a wider range of populations.

Hedgehog signaling has a key role in hair follicle development, as well as in induction of the most common cancer in individuals of European descent, basal cell carcinoma (BCC). A new study shows that BCCs strongly resemble embryonic hair follicles and that BCC induction requires active Wnt/β-catenin signaling.

Defining the molecular nature of the genetic risk of psychiatric disorders has been notoriously difficult. Now, a flurry of genome-wide association studies for schizophrenia and bipolar disorder provides preliminary evidence for replicated signals.

Michael O'Donovan and colleagues present a genome-wide association study of schizophrenia in 479 cases and 2,937 controls, followed by replication in several cohorts. They report evidence for association for a susceptibility allele near ZNF804A.

Pamela Sklar and colleagues report a genome-wide association study of bipolar disorder and identify variants in the genes encoding ankyrin-3 and the alpha-1C subunit of the L-type voltage-gated calcium channel as increasing risk.

Patrick Gaffney and colleagues report results of a genome-wide association study for systemic lupus erythematosus (SLE), identifying variants in the TNFAIP3 region on 6q23 that are strongly associated with the disease. In a related study, Lindsey Criswell and colleagues report a similar association between variants near TNFAIP3 and SLE. The same region on 6q23 has recently been associated with rheumatoid arthritis, but only a subset of risk alleles in this region seem to be common to both diseases.

Lindsey Criswell and colleagues report an association between three independent variants near TNFAIP3 and systemic lupus erythematosus (SLE). In a related study, Patrick Gaffney and colleagues report results of a genome-wide association study for SLE, also identifying variants in the TNFAIP3 region on 6q23 that are strongly associated with the disease. The same region on 6q23 has recently been associated with rheumatoid arthritis, but only a subset of risk alleles in this region seem to be common to both diseases.

Kerstin Kutsche and colleagues report that mutations in CASK cause an X-linked brain malformation marked by microcephaly and hypoplasia of the brainstem and cerebellum. CASK encodes a scaffolding protein that is thought to play important roles in neuronal development and synaptic trafficking.

Augustine Kong and colleagues describe an approach for phasing SNPs into long haplotypes spanning multiple blocks of linkage disequilibrium. The method, termed long-range phasing, can be also used to impute long haplotypes for ungenotyped individuals.

Evan Eichler and colleagues present a sequence assembly of the inverted H2 haplotype of human chromosome 17q21.31 and show that the inversion is polymorphic in other great ape species. Their analyses suggest that the H2 configuration represents the ancestral state in great apes and that inversions have occurred independently in the human and chimpanzee lineages.

Peter Gallant and colleagues show that the control of endoreplication and cell competition in Drosophila are activities of Myc proto-oncogene in vivo that do not require the association with its Max binding partner. Further, a Myc derivative that does not interact with Max retains substantial biological activity, and Myc can control RNA polymerase III independently of Max.

Masato Kasuga and colleagues and Shiro Maeda and colleagues each report the independent identification of SNPs in KCNQ1 associated with type 2 diabetes in the Japanese population. Each group replicated the associations in other populations of East Asian and European descent.

Masato Kasuga and colleagues and Shiro Maeda and colleagues each report the independent identification of SNPs in KCNQ1 associated with type 2 diabetes in the Japanese population. Each group replicated the associations in other populations of East Asian and European descent.

Stefan Schreiber and colleagues report the results of a genome-wide association study for sarcoidosis, a complex chronic inflammatory disorder. Variants near ANXA11 and PLAC9 are associated with elevated risk of the disease, with ANXA11 as the stronger candidate.

Mark Daly, Ramnik Xavier and colleagues report that a 20-kb deletion polymorphism upstream of IRGM is associated with altered IRGM expression and Crohn's disease. They also show that manipulation of IRGM levels in cells modulated the efficiency of autophagic responses to internalized bacteria, suggesting a mechanism by which the deletion variant might influence disease risk.

Frank Baas and colleagues report mutations in three of the four subunits of the tRNA-splicing endonuclease complex in families with two subtypes of pontocerebellar hypoplasia. The findings implicate tRNA processing in neurological disorders.

Valerie Cormier-Daire and colleagues report mutations in ADAMTSL2 in geleophysic dysplasia, a connective tissue disorder. The authors present evidence that ADAMTSL2 is an extracellular matrix protein regulating the bioavailability of TGF-β.

Gil McVean and colleagues examine recombination hot spots in the human genome, using new search methods and drawing on HapMap II to identify an extended family of hot spot–associated motifs. They report a common sequence motif estimated to be found in ∼40% of recombination hot spots.

Andrzej Dlugosz and colleagues report that Hedgehog-dependent skin tumors require canonical Wnt signaling for their development.

Miltos Tsiantis and colleagues examine leaf formation in Arabidopsis thaliana, which has simple, undivided leaves, and Cardamine hirsuta, which has a subdivided leaf blade with individual leaflets. Using genetics, marker gene expression and cell lineage tracing, the authors show that lateral leaflet formation in C. hirsuta requires establishment of growth foci that form after leaf initiation.