Brain-derived neurotrophic factor (BDNF) modulates hippocampal plasticity and hippocampal-dependent memory in cell models and in animals. We examined the effects of a valine (val) to methionine (met) substitution in the 5' pro-region of the human BDNF protein. In human subjects, the met allele was associated with poorer episodic memory, abnormal hippocampal activation assayed with fMRI, and lower hippocampal n-acetyl aspartate (NAA), assayed with MRI spectroscopy. Neurons transfected with met-BDNF-GFP showed lower depolarization-induced secretion, while constitutive secretion was unchanged. Furthermore, met-BDNF-GFP failed to localize to secretory granules or synapses. These results demonstrate a role for BDNF and its val/met polymorphism in human memory and hippocampal function and suggest val/met exerts these effects by impacting intracellular trafficking and activity-dependent secretion of BDNF.

Age-related macular degeneration (AMD) is the most frequent cause of irreversible blindness in the elderly in developed countries. Our previous studies implicated activation of complement in the formation of drusen, the hallmark lesion of AMD. Here, we show that factor H (HF1), the major inhibitor of the alternative complement pathway, accumulates within drusen and is synthesized by the retinal pigmented epithelium. Because previous linkage analyses identified chromosome 1q25-32, which harbors the factor H gene (HF1͞CFH), as an AMD susceptibility locus, we analyzed HF1 for genetic variation in two independent cohorts comprised of Ϸ900 AMD cases and 400 matched controls. We found association of eight common HF1 SNPs with AMD; two common missense variants exhibit highly significant associations (I62V, 2 ‫؍‬ 26.1 and P ‫؍‬ 3.2 ؋ 10 ؊7 and Y402H, 2 ‫؍‬ 54.4 and P ‫؍‬ 1.6 ؋ 10 ؊13 ). Haplotype analysis reveals that multiple HF1 variants confer elevated or reduced risk of AMD. One common at-risk haplotype is present at a frequency of 50% in AMD cases and 29% in controls [odds ratio (OR) ‫؍‬ 2.46, 95% confidence interval (1.95-3.11)]. Homozygotes for this haplotype account for 24% of cases and 8% of controls [OR ‫؍‬ 3.51, 95% confidence interval (2.13-5.78)]. Several protective haplotypes are also identified (OR ‫؍‬ 0.44 -0.55), further implicating HF1 function in the pathogenetic mechanisms underlying AMD. We propose that genetic variation in a regulator of the alternative complement pathway, when combined with a triggering event, such as infection, underlie a major proportion of AMD in the human population.A ge-related macular degeneration (AMD) is the leading cause of irreversible vision loss (1, 2), affecting Ϸ50 million individuals worldwide. AMD is characterized by a progressive loss of central vision attributable to degenerative and neovascular changes that occur at the interface between the neural retina and the underlying choroid. At this location are the retinal photoreceptors, the retinal pigmented epithelium (RPE), a basement membrane complex known as Bruch's membrane (BM) and a network of choroidal capillaries.The prevailing view is that AMD is a complex disorder stemming from the interaction of multiple genetic and environmental risk factors (3,4). Familial aggregation studies indicate that a genetic contribution can be identified in up to 25% of the cases (5). Thus, AMD appears to be a product of the interaction between multiple susceptibility loci rather than a collection of single-gene disorders. The number of loci involved, the attributable risk conferred, and the interactions between various loci remain obscure.

Viral Link to Chronic Fatigue Chronic fatigue syndrome (CFS) is a complex and debilitating disorder that is often linked to immune system dysfunction but whose cause(s) remain mysterious. Lombardi et al. (p. 585 , published online 8 October; see the Perspective by Coffin and Stoye ) now present a tantalizing new lead. In blood samples from 101 patients with well-documented CFS, over two-thirds (68) contained DNA from a recently described human gammaretrovirus, xenotropic murine leukemia virus–related virus (XMRV), which possesses sequence similarity to a murine leukemia virus. Cell culture assays confirmed that XMRV derived from CFS patient plasma and from T and B lymphocytes was infectious. Although the correlation with CFS is striking, whether the virus plays a causal role in the disorder remains to be determined. Interestingly, nearly 4% of the 218 healthy donors tested were positive for XMRV, which suggests that this virus—whose pathogenic potential is unknown—may be present in a significant proportion of the general population.

Age-related macular degeneration (AMD) is the most common form of irreversible blindness in developed countries 1,2 . Variants in the factor H gene (CFH, also known as HF1), which encodes a major inhibitor of the alternative complement pathway, are associated with the risk for developing AMD [3][4][5][6][7][8] . Here we test the hypothesis that variation in genes encoding other regulatory proteins of the same pathway is associated with AMD. We screened factor B (BF) and complement component 2 (C2) genes, located in the major histo-compatibility complex class III region, for genetic variation in two independent cohorts comprising ~900 individuals with AMD and ~400 matched controls. Haplotype analyses identify a statistically significant common risk haplotype (H1) and two protective haplotypes. The L9H variant of BF and the E318D variant of C2 (H10), as well as a variant in intron 10 of C2 and the R32Q variant of BF (H7), confer a significantly reduced risk of AMD (odds ratio = 0. 45 and 0.36, respectively). Combined analysis of the C2 and BF haplotypes and CFH variants shows that variation in the two loci can predict the clinical outcome in 74% of the affected individuals and 56% of the controls. These data expand and refine our understanding of the genetic risk for AMD.Correspondence should be addressed to R.A. (rla22@columbia.edu) or M.D. (dean@ncifcrf.gov). Note: Supplementary information is available on the Nature Genetics website. AUTHOR CONTRIBUTION STATEMENTThe AMD Genetics Clinical Study Group includes Stanley Chang, Lawrence A. Yannuzzi, John C. Merriam and Irene Barbazetto (Department of Ophthalmology, Columbia University, New York); Leonid E. Lerner (F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania School of Medicine, Philadelphia) and Stephen Russell, Jamal Hoballah, Jill Hageman and Heather Stockman (Department of Ophthalmology and Visual Sciences, Center for Macular Degeneration, University of Iowa, Iowa City, Iowa, USA). COMPETING INTERESTS STATEMENTThe authors declare competing financial interests (see the Nature Genetics website for details).Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/ NIH Public Access Inflammation has a central role in the pathobiology of AMD 9-14 . Dysfunction of the complement pathway is proposed to induce significant damage to macular cells, leading to atrophy, degeneration and the elaboration of choroidal neovascular membranes 3,[15][16][17] . Activation of the alternative pathway is initiated by cleavage of C3b-bound factor B (BF), resulting in the formation of the C3Bb complex (C3 convertase). This complex is stabilized by properdin, whereas its dissociation is accelerated by regulatory proteins, including complement factor H (CFH), the major inhibitor of the alternative complement pathway. As CFH haplotypes are associated with AMD 3 , we hypothesized that the same may be true for activators of the same pathway, such as complement factor B (BF). BF and compl...

Comparative analysis of the sea urchin genome has broad implications for the primitive state of deuterostome host defense and the genetic underpinnings of immunity in vertebrates. The sea urchin has an unprecedented complexity of innate immune recognition receptors relative to other animal species yet characterized. These receptor genes include a vast repertoire of 222 Toll-like receptors, a superfamily of more than 200 NACHT domain-leucine-rich repeat proteins (similar to nucleotide-binding and oligomerization domain (NOD) and NALP proteins of vertebrates), and a large family of scavenger receptor cysteine-rich proteins. More typical numbers of genes encode other immune recognition factors. Homologs of important immune and hematopoietic regulators, many of which have previously been identified only from chordates, as well as genes that are critical in adaptive immunity of jawed vertebrates, also are present. The findings serve to underscore the dynamic utilization of receptors and the complexity of immune recognition that may be basal for deuterostomes and predicts features of the ancestral bilaterian form.

Many cancer-associated genes remain to be identified to clarify the underlying molecular mechanisms of cancer susceptibility and progression. Better understanding is also required of how mutations in cancer genes affect their products in the context of complex cellular networks. Here we have used a network modeling strategy to identify genes potentially associated with higher risk of breast cancer. Starting with four known genes encoding tumor suppressors of breast cancer, we combined gene expression profiling with functional genomic and proteomic (or 'omic') data from various species to generate a network containing 118 genes linked by 866 potential functional associations. This network shows higher connectivity than expected by chance, suggesting that its components function in biologically related pathways. One of the components of the network is HMMR, encoding a centrosome subunit, for which we demonstrate previously unknown functional associations with the breast cancer-associated gene BRCA1. Two case-control studies of incident breast cancer indicate that the HMMR locus is associated with higher risk of breast cancer in humans. Our network modeling strategy should be useful for the discovery of additional cancer-associated genes.

Tripartite motif (TRIM) proteins are composed of RING, B-box 2, and coiled coil domains. Some TRIM proteins, such as TRIM5␣, also possess a carboxy-terminal B30.2(SPRY) domain and localize to cytoplasmic bodies. TRIM5␣ has recently been shown to mediate innate intracellular resistance to retroviruses, an activity dependent on the integrity of the B30.2 domain, in particular primate species. An examination of the sequences of several TRIM proteins related to TRIM5 revealed the existence of four variable regions (v1, v2, v3, and v4) in the B30.2 domain. Species-specific variation in TRIM5␣ was analyzed by amplifying, cloning, and sequencing nonhuman primate TRIM5 orthologs. Lineage-specific expansion and sequential duplication occurred in the TRIM5␣ B30.2 v1 region in Old World primates and in v3 in New World monkeys. We observed substitution patterns indicative of selection bordering these particular B30.2 domain variable elements. These results suggest that occasional, complex changes were incorporated into the TRIM5␣ B30.2 domain at discrete time points during the evolution of primates. Some of these time points correspond to periods during which primates were exposed to retroviral infections, based on the appearance of particular endogenous retroviruses in primate genomes. The results are consistent with a role for TRIM5␣ in innate immunity against retroviruses.

In mammals, the neuropeptide vasopressin is a key molecule for complex emotional and social behaviours. Two microsatellite polymorphisms, RS1 and RS3, near the promoter of AVPR1A, encoding the receptor subtype most heavily implicated in behaviour regulation, have been linked to autism and behavioural traits. However, the impact of these variants on human brain function is unknown. Here we show that human amygdala function is strongly associated with genetic variation in AVPR1A. Using an imaging genetics approach in a sample of 121 volunteers studied with an emotional face-matching paradigm, we found that differential activation of amygdala is observed in carriers of risk alleles for RS3 and RS1. Alleles in RS1 previously reported to be significantly over-and undertransmitted to autistic probands showed opposing effects on amygdala activation. Furthermore, we show functional difference in human brain between short and long repeat lengths that mirror findings recently obtained in a corresponding variant in voles. Our results indicate a neural mechanism mediating genetic risk for autism through an impact on amygdala signalling and provide a rationale for exploring therapeutic strategies aimed at abnormal amygdala function in this disorder.