Inherited defects in pedigree dogs. Part 2: Disorders that are not related to breed standards

Recent debate concerning health problems in pedigree animals has highlighted gaps in current knowledge of the prevalence, severity and welfare implications of deleterious inherited traits within the pedigree dog population. In this second part of a two-part review, inherited disorders in the top 50 UK Kennel Club registered breeds were researched using systematic searches of existing databases. A set of inclusion and exclusion criteria, including an evidence strength scale (SEHB), were applied to search results. A total of 312 non-conformation linked inherited disorders was identified, with German shepherd dogs and Golden retrievers associated with the greatest number of disorders. The most commonly reported mode of inheritance was autosomal recessive (71%; 57 breed-disorder combinations), and the most common primarily affected body system was the nervous sensory system. To provide a true assessment of the scale of inherited disorders in the pedigree dogs studied more effort is required to collect accurate prevalence data.

Inherited defects in pedigree dogs. Part 1: Disorders related to breed standards

The United Kingdom pedigree-dog industry has faced criticism because certain aspects of dog conformation Stipulated in the UK Kennel Club breed standards have a detrimental impact oil dog welfare. A review of conformation-related disorders was carried out in the top 50 UK Kennel Club registered breeds using systematic searches of existing information A novel index to score severity of disorders along a single-scale was also developed and used to conduct statistical analyses to determine the factors affecting reported breed predisposition to defects According to the literature searched, each of the top 50 breeds was found to have at least one aspect of its conformation predisposing it to a disorder. and 84 disorders were either directly or indirectly associated with conformation. The Miniature poodle, Bulldog. Pug and Basset hound had most associations with conformation-related disorders. Further research oil prevalence and severity is required to assess the impact of different disorders oil the welfare of affected breeds (C) 2009 Elsevier Ltd. All rights reserved

Unravelling the genetic basis of renal diseases; from single gene to multifactorial disorders

Chronic kidney disease is common with up to 5% of the adult population reported to have an estimated glomerular filtration rate of

Association Analysis of the PIP4K2A Gene on Chromosome 10p12 and Schizophrenia in the Irish Study of High Density Schizophrenia Families (ISHDSF) and the Irish Case-Control Study of Schizophrenia (ICCSS)

Molecular studies support pharmacological evidence that phosphoinositide signaling is perturbed in schizophrenia and bipolar disorder. The phosphatidylinositol-4-phosphate-5-kinase type-II alpha (PIP4K2A) gene is located on chromosome 10p12. This region has been implicated in both diseases by linkage, and PIP4K2A directly by association. Given linkage evidence in the Irish Study of High Density Schizophrenia Families (ISHDSF) to a region including 10p12, we performed an association study between genetic variants at PIP4K2A and disease. No association was detected through single-marker or haplotype analysis of the whole sample. However, stratification into families positive and negative for the ISHDSF schizophrenia high-risk haplotype (HRH) in the DTNBP1 gene and re-analysis for linkage showed reduced amplitude of the 10p12 linkage peak in the DTNBP1 HRH positive families. Association analysis of the stratified sample showed a trend toward association of PIP4K2A SNPs rs1417374 and rs1409395 with schizophrenia in the DTNBP1 HRH positive families. Despite this apparent paradox, our data may therefore suggest involvement of PIP4K2A in schizophrenia in those families for whom genetic variation in DTNBP1 appears also to be a risk factor. This trend appears to arise from under-transmission of common alleles to female cases. Follow-up association analysis in a large Irish schizophrenia case-control control sample (ICCSS) showed significant association with disease of a haplotype comprising these same SNPs rs1417374-rs1409395, again more so in affected females, and in cases with negative family history of the disease. This study supports a minor role for PIP4K2A in schizophrenia etiology in the Irish population. (C) 2009 Wiley-Liss, Inc.

Meta-analysis of 32 genome-wide linkage studies of schizophrenia

A genome scan meta-analysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (P-SR) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for 'aggregate' genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies. Molecular Psychiatry (2009) 14, 774-785; doi:10.1038/mp.2008.135; published online 30 December 2008

Novel linkage to chromosome 20p using latent classes of psychotic illness in 270 Irish high-density families

Background: Several lines of evidence suggest that the clinical heterogeneity of schizophrenia is due to genetic heterogeneity. Genetic heterogeneity may decrease the signal-to-noise ratio in linkage and association studies. Therefore, linkage studies of clinically homogeneous classes of psychotic illness may result in greater power to detect at least some loci.

Diagnostic and prognostic biomarker discovery strategies for autoimmune disorders.

Current clinical, laboratory or radiological parameters cannot accurately diagnose or predict disease outcomes in a range of autoimmune disorders. Biomarkers which can diagnose at an earlier time point, predict outcome or help guide therapeutic strategies in autoimmune diseases could improve clinical management of this broad group of debilitating disorders. Additionally, there is a growing need for a deeper understanding of multi-factorial autoimmune disorders. Proteomic platforms offering a multiplex approach are more likely to reflect the complexity of autoimmune disease processes. Findings from proteomic based studies of three distinct autoimmune diseases are presented and strategies compared. It is the authors' view that such approaches are likely to be fruitful in the movement of autoimmune disease treatment away from reactive decisions and towards a preventative stand point.

Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2 alpha gain-of-function mutation

The hypoxia-inducible factors (HIFs; isoforms HIF-1 alpha, HIF-2 alpha, HIF-3 alpha) mediate many responses to hypoxia. Their regulation is principally by oxygen-dependent degradation, which is initiated by hydroxylation of specific proline residues followed by binding of von Hippel-Lindau (VHL) protein. Chuvash polycythemia is a disorder with elevated HIF. It arises through germline homozygosity for hypomorphic VHL alleles and has a phenotype of hematological, cardiopulmonary, and metabolic abnormalities. This study explores the phenotype of two other HIF pathway diseases: classic VHL disease and HIF-2 alpha gain-of-function mutation. No cardiopulmonary abnormalities were detected in classic VHL disease. HIF-2 alpha gain-of-function mutations were associated with pulmonary hypertension, increased cardiac output, increased heart rate, and increased pulmonary ventilation relative to metabolism. Comparison of the HIF-2 alpha gain-of-function responses with data from studies of Chuvash polycythemia suggested that other aspects of the Chuvash phenotype were diminished or absent. In classic VHL disease, patients are germline heterozygous for mutations in VHL, and the present results suggest that a single wild-type allele for VHL is sufficient to maintain normal cardiopulmonary function. The HIF-2 alpha gain-of-function phenotype may be more limited than the Chuvash phenotype either because HIF-1 alpha is not elevated in the former condition, or because other HIF-independent functions of VHL are perturbed in Chuvash polycythemia.-Formenti, F., Beer, P. A., Croft, Q. P. P., Dorrington, K. L., Gale, D. P., Lappin, T. R. J., Lucas, G. S., Maher, E. R., Maxwell, P. H., McMullin, M. F., O'Connor, D. F., Percy, M. J., Pugh, C. W., Ratcliffe, P. J., Smith, T. G., Talbot, N. P., Robbins, P. A. Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2 alpha gain-of-function mutation. FASEB J. 25, 2001-2011 (2011). www.fasebj.org