Deciphering the genetic landscape of Alzheimer disease (AD) is essential to define the pathophysiological pathways involved and to successfully translate genomics to potential tailored medical care. To generate the most complete knowledge of the AD genetics, we developed through the European Alzheimer Disease BioBank (EADB) consortium a discovery meta-analysis of genome-wide association studies (GWAS) based on a new large case-control study and previous GWAS (in total 39,106 clinically diagnosed cases, 46,828 proxy-AD cases and 401,577 controls) with the most promising signals followed-up in independent samples (18,063 cases and 23,207 controls). In addition to 34 known AD loci, we report here the genome-wide significant association of 31 new loci with the risk of AD. Pathway-enrichment analyses strongly indicated the involvement of gene sets related to amyloid and Tau, but also highlighted microglia, in which increased gene expression corresponds to more significant AD risk. In addition, we successfully prioritized candidate genes in the majority of our new loci, with nine being primarily expressed in microglia. Finally, we observed that a polygenic risk score generated from this new genetic landscape was strongly associated with the risk of progression from mild cognitive impairment (MCI) to dementia (4,609 MCI cases of whom 1,532 converted to dementia), independently of age and the APOE e4 allele.

Barramundi (Lates calcarifer) is a teleost of the superorder Acanthopterygii. Barramundi IGF-I cDNA was cloned and the distribution of alternative transcripts in various barramundi tissues was investigated using rt-PCR and RPA. It was demonstrated that in barramundi tissues, IGF-I mRNAs were represented by two transcripts corresponding to the reported salmonid Ea-2 and Ea-4. The acute effect of GH on hepatic IGF-I mRNA levels was investigated. Seven hours after intraperitonal administration of either 6 micrograms of recombinant bream GH/g body weight or saline, no significant increase in the levels of either of the two transcripts could be observed. The presence of GH receptors in the barramundi liver was demonstrated in binding assays using recombinant bream GH and liver membrane preparations. An analysis of a barramundi IGF-I genomic sequence encompassing the three exons that encode the E domain suggested that the pattern of splice site utilization is determined by the degree of homology of the splicing signals to the consensus splice site sequences.