Novel protective and risk loci in hip dysplasia in German Shepherds.

Canine hip dysplasia is a common, non-congenital, complex and hereditary disorder. It can inflict severe pain via secondary osteoarthritis and lead to euthanasia. An analogous disorder exists in humans. The genetic background of hip dysplasia in both species has remained ambiguous despite rigorous studies. We aimed to investigate the genetic causes of this disorder in one of the high-risk breeds, the German Shepherd. We performed genetic analyses with carefully phenotyped case-control cohorts comprising 525 German Shepherds. In our genome-wide association studies we identified four suggestive loci on chromosomes 1 and 9. Targeted resequencing of the two loci on chromosome 9 from 24 affected and 24 control German Shepherds revealed deletions of variable sizes in a putative enhancer element of the NOG gene. NOG encodes for noggin, a well-described bone morphogenetic protein inhibitor affecting multiple developmental processes, including joint development. The deletion was associated with the healthy controls and mildly dysplastic dogs suggesting a protective role against canine hip dysplasia. Two enhancer variants displayed a decreased activity in a dual luciferase reporter assay. Our study identifies novel loci and candidate genes for canine hip dysplasia, with potential regulatory variants in the NOG gene. Further research is warranted to elucidate how the identified variants affect the expression of noggin in canine hips, and what the potential effects of the other identified loci are.

Evidence for genetic regulation of the human parieto-occipital 10-Hz rhythmic activity.

Several functional and morphological brain measures are partly under genetic control. The identification of direct links between neuroimaging signals and corresponding genetic factors can reveal cellular-level mechanisms behind the measured macroscopic signals and contribute to the use of imaging signals as probes of genetic function. To uncover possible genetic determinants of the most prominent brain signal oscillation, the parieto-occipital 10-Hz alpha rhythm, we measured spontaneous brain activity with magnetoencephalography in 210 healthy siblings while the subjects were resting, with eyes closed and open. The reactivity of the alpha rhythm was quantified from the difference spectra between the two conditions. We focused on three measures: peak frequency, peak amplitude and the width of the main spectral peak. In accordance with earlier electroencephalography studies, spectral peak amplitude was highly heritable (h(2)  > 0.75). Variance component-based analysis of 28 000 single-nucleotide polymorphism markers revealed linkage for both the width and the amplitude of the spectral peak. The strongest linkage was detected for the width of the spectral peak over the left parieto-occipital cortex on chromosome 10 (LOD = 2.814, nominal P < 0.03). This genomic region contains several functionally plausible genes, including GRID1 and ATAD1 that regulate glutamate receptor channels mediating synaptic transmission, NRG3 with functions in brain development and HRT7 involved in the serotonergic system and circadian rhythm. Our data suggest that the alpha oscillation is in part genetically regulated, and that it may be possible to identify its regulators by genetic analyses on a realistically modest number of samples.

Identification of a common risk haplotype for canine idiopathic epilepsy in the ADAM23 gene.

BACKGROUND: Idiopathic epilepsy is a common neurological disease in human and domestic dogs but relatively few risk genes have been identified to date. The seizure characteristics, including focal and generalised seizures, are similar between the two species, with gene discovery facilitated by the reduced genetic heterogeneity of purebred dogs. We have recently identified a risk locus for idiopathic epilepsy in the Belgian Shepherd breed on a 4.4 megabase region on CFA37. RESULTS: We have expanded a previous study replicating the association with a combined analysis of 157 cases and 179 controls in three additional breeds: Schipperke, Finnish Spitz and Beagle (p(c) = 2.9e-07, p(GWAS) = 1.74E-02). A targeted resequencing of the 4.4 megabase region in twelve Belgian Shepherd cases and twelve controls with opposite haplotypes identified 37 case-specific variants within the ADAM23 gene. Twenty-seven variants were validated in 285 cases and 355 controls from four breeds, resulting in a strong replication of the ADAM23 locus (p(raw) = 2.76e-15) and the identification of a common 28 kb-risk haplotype in all four breeds. Risk haplotype was present in frequencies of 0.49-0.7 in the breeds, suggesting that ADAM23 is a low penetrance risk gene for canine epilepsy. CONCLUSIONS: These results implicate ADAM23 in common canine idiopathic epilepsy, although the causative variant remains yet to be identified. ADAM23 plays a role in synaptic transmission and interacts with known epilepsy genes, LGI1 and LGI2, and should be considered as a candidate gene for human epilepsies.

Increased expression of MERTK is associated with a unique form of canine retinopathy.

Progressive retinal degenerations are among the most common causes of blindness both in human and in dogs. Canine progressive retinal atrophy (PRA) resembles human retinitis pigmentosa (RP) and is typically characterized by a progressive loss of rod photoreceptors followed by a loss of cone function. The disease gradually progress from the loss of night and day vision to a complete blindness. We have recently described a unique form of retinopathy characterized by the multifocal gray/brown discoloration and thinning of the retina in the Swedish Vallhund (SV) breed. We aimed to identify the genetic cause by performing a genome wide association analysis in a cohort of 18 affected and 10 healthy control dogs using Illumina's canine 22k SNP array. We mapped the disease to canine chromosome 17 (p = 7.7×10(-5)) and found a 6.1 Mb shared homozygous region in the affected dogs. A combined analysis of the GWAS and replication data with additional 60 dogs confirmed the association (p = 4.3×10(-8), OR = 11.2 for homozygosity). A targeted resequencing of the entire associated region in four cases and four controls with opposite risk haplotypes identified several variants in the coding region of functional candidate genes, such as a known retinopathy gene, MERTK. However, none of the identified coding variants followed a compelling case- or breed-specific segregation pattern. The expression analyses of four candidate genes in the region, MERTK, NPHP1, ANAPC1 and KRCC1, revealed specific upregulation of MERTK in the retina of the affected dogs. Collectively, these results indicate that the retinopathy is associated with overexpression of MERTK, however further investigation is needed to discover the regulatory mutation for the better understanding of the disease pathogenesis. Our study establishes a novel gain-of-function model for the MERTK biology and provides a therapy model for retinopathy MERTK inhibitors. Meanwhile, a marker-based genetic counseling can be developed to revise breeding programs.

Environmental effects on compulsive tail chasing in dogs.

Obsessive Compulsive Disorder (OCD) is a neuropsychiatric disorder observed both in humans and animals. Examples of Canine Compulsive Disorder (CD) include excessive tail chasing (TC), light/shadow chasing and flank sucking. We performed a questionnaire survey to investigate the characteristics of compulsive (TC) and its possible associations with environmental correlates and personality in a pet population of 368 dogs from four dog breeds. We observed an early onset of TC at 3-6 months of age and a large variation in TC frequency in all breeds, with an overrepresentation of milder cases. Almost half of the TC dogs showed lowered responsiveness during bouts and displayed also other types of compulsions more often than the controls. Interestingly, dogs that received dietary supplements, especially vitamins and minerals, expressed less TC compared to dogs that did not receive any supplements. Neutered females had less TC, suggesting an influence of ovarian hormones on TC. Tail chasers were shyer and had separated earlier from their mothers than the controls. Finally, our genetic study did not find an association between TC and CDH2, a locus previously associated with the canine flank sucking compulsion. In conclusion, the early-onset and the variable nature of the repetitive behaviour, which is affected by environmental factors such as micronutrients, neutering and maternal care, share several similar components between canine and human compulsions and supports canine TC as a model for human OCD.