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A questionnaire instrument for obtaining quantitative behavioral evaluations of pet cats from cat owners was developed and validated. Exploratory Factor Analysis of 2608 questionnaire responses to 149 behavioral questions/items extracted a total of 23 distinct factors that measured most of the more common dimensions of cat behavior. Seventeen of the 23 factors demonstrated adequate-high internal reliability (Cronbach's alpha=0.712-0.923). Questionnaire validation was accomplished by determining: (a) whether owners' subjective ratings of the severity of their cat's behavior problems were associated with cats' actual scores on expected questionnaire factors, (b) whether expected associations between specific demographic and/or lifestyle characteristics and behavior were confirmed by cats' factor or item scores on the questionnaire, and (c) whether breed rankings based on owner-reported factor scores matched those previously derived from the opinions of experts (veterinarians). The results of these various tests confirmed the overall construct validity of the questionnaire., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Although the term quantitative trait locus (QTL) strictly refers merely to a genetic variant that causes changes in a quantitative phenotype such as height, QTL analysis more usually describes techniques used to study oligogenic or polygenic traits where each identified locus contributes a relatively small amount to the genetic determination of the trait, which may be categorical in nature. Originally, too, it would be clear that it covered segregation and genetic linkage analysis, but now genetic association analysis in a genome-wide SNP or sequencing experiment would be the commonest application. The same biometrical genetic statistical apparatus used in this setting-analysis of variance, linear or generalized linear mixed models-can actually be applied to categorical phenotypes, as well as to multiple traits simultaneously, dealing with and taking advantage of genetic pleiotropy. Most recently, they are being used to make inferences about population and evolutionary genetics, with applications ranging from human disease to control of disease-causing organisms. Several computer software packages make it relatively straightforward to fit these statistically complex models to the large amounts of genotype and phenotype data routinely collected today.

Genetic variants associated with asthma pathogenesis and altered response to drug therapy are discussed. Many studies implicate polymorphisms in genes encoding the enzymes responsible for leukotriene synthesis and intracellular signaling through activation of seven transmembrane domain receptors, such as the cysteinyl leukotriene 1 (CYSLTR1) and 2 (CYSLTR2) receptors. The leukotrienes are polyunsaturated lipoxygenated eicosatetraenoic acids that exhibit a wide range of pharmacological and physiological actions. Of the three enzymes involved in the formation of the leukotrienes, arachidonate 5 lipoxygenase 5 (ALOX5), leukotriene C4 synthase (LTC4S), and leukotriene hydrolase (LTA4H) are all polymorphic. These polymorphisms often result in variable production of the CysLTs (LTC4, LTD4, and LTE4) and LTB4. Variable number tandem repeat sequences located in the Sp1-binding motif within the promotor region of the ALOX5 gene are associated with leukotriene burden and bronchoconstriction independent of asthma risk. A 444A > C SNP polymorphism in the LTC4S gene, encoding an enzyme required for the formation of a glutathione adduct at the C-6 position of the arachidonic acid backbone, is associated with severe asthma and altered response to the CYSLTR1 receptor antagonist zafirlukast. Genetic variability in the CysLT pathway may contribute additively or synergistically to altered drug responses. The 601 A > G variant of the CYSLTR2 gene, encoding the Met201Val CYSLTR2 receptor variant, is associated with atopic asthma in the general European population, where it is present at a frequency of ∼2.6%. The variant was originally found in the founder population of Tristan da Cunha, a remote island in the South Atlantic, in which the prevalence of atopy is approximately 45% and the prevalence of asthma is 36%. In vitro work showed that the atopy-associated Met201Val variant was inactivating with respect to ligand binding, Ca 2+ flux and inositol phosphate generation. In addition, the CYSLTR1 gene, located at Xq13-21.1, has been associated with atopic asthma. The activating Gly300Ser CYSLTR1 variant is discussed. In addition to genetic loci, risk for asthma may be influenced by environmental factors such as smoking. The contribution of CysLT pathway gene sequence variants to atopic asthma is discussed in the context of other genes and environmental influences known to influence asthma.

Background: Aboriginal Australians are at high risk of cardiovascular, metabolic and renal diseases, resulting in a marked reduction in life expectancy when compared to the rest of the Australian population. This is partly due to recognized environmental and lifestyle risk factors, but a contribution of genetic susceptibility is also likely., Methods: Using results from a comprehensive survey of one community (N = 1350 examined individuals), we have tested for familial aggregation of plasma glucose, arterial blood pressure, albuminuria (measured as urinary albumin to creatinine ratio, UACR) and estimated glomerular filtration rate (eGFR), and quantified the contribution of variation at four candidate genes (ACE; TP53; ENOS3; MTHFR)., Results: In the subsample of 357 individuals with complete genotype and phenotype data we showed that both UACR (h 2  = 64%) and blood pressure (sBP h 2  = 29%, dBP, h 2  = 11%) were significantly heritable. The ACE insertion-deletion (P = 0.0009) and TP53 codon72 polymorphisms (P = 0.003) together contributed approximately 15% of the total heritability of UACR, with an effect of ACE genotype on BP also clearly evident., Conclusions: While the effects of the ACE insertion-deletion on risk of renal disease (especially in the setting of diabetes) are well recognized, this is only the second study to implicate p53 genotype as a risk factor for albuminuria - the other being an earlier study we performed in a different Aboriginal community (McDonald et al., J Am Soc Nephrol 13: 677-83, 2002). We conclude that there are significant genetic contributions to the high prevalence of chronic diseases observed in this population.

Objective: The findings of genetic, imaging and neuropsychological studies of attention-deficit hyperactivity disorder (ADHD) are mixed. To understand why this might be the case we use both dimensional and categorical symptom measurement to provide alternate and detailed perspectives of symptom expression., Method: Interviewers collected ADHD, conduct problems (CP) and sociodemographic data from 3793 twins and their siblings aged 22 to 49 (M = 32.6). We estimate linear weighting of symptoms across ADHD and CP items. Latent class analyses and regression describe associations between measured variables, environmental risk factors and subsequent disadvantage. Additionally, the clinical relevance of each class was estimated., Results: Five classes were found for women and men; few symptoms, hyperactive-impulsive, CP, inattentive, combined symptoms with CP. Women within the inattentive class reported more symptoms and reduced emotional health when compared to men and to women within other latent classes. Women and men with combined ADHD symptoms reported comorbid conduct problems but those with either inattention or hyperactivity-impulsivity only did not., Conclusion: The dual perspective of dimensional and categorical measurement of ADHD provides important detail about symptom variation across sex and with environmental covariates., (© The Author(s) 2013.)

Maturational changes in behavior, and the possible influence of the puppy-raising environment on behavioral development, were investigated in a total sample of 978 prospective guide dogs belonging to four different breeds/crosses. All dogs belonged to the same guide dog organization, and had been exposed to similar early environmental influences prior to being assigned to puppy-raising households at 7-8 weeks of age. Behavioral data were collected from puppy raisers when the dogs were 6 and 12 months old using the C-BARQ(©), a standardized, validated, and widely used survey instrument that measures the frequency and/or severity of most common behavior problems in dogs. Information about the puppy-raising environment was obtained from puppy raisers using a standardized questionnaire shortly before the dogs were returned to the guide dog organization for training. Data were analyzed using both univariate and multivariate statistics (binary logistic generalized estimating equations modeling and generalized linear modeling). The findings demonstrated specific maturational changes in behavior between 6 and 12 months of age. In particular, German Shepherd dogs displayed an increase in stranger-directed aggression compared with the other breeds/crosses between 6 and 12 months of age. Several aspects of the puppy-raising environment were associated with puppies' C-BARQ scores at 12 months of age. In particular, growing up in households with more experienced puppy raisers, and in the company of at least one other dog, were both associated with positive effects on a number of puppy behaviors. By contrast, puppies that had been frightened by a person or threatened by another unfamiliar dog showed significantly worse scores for fear of strangers and dogs, respectively. Being frightened by a person, being reared by less experienced puppy raisers, and/or in households without other pets were associated with less successful training outcomes. The relevance of these findings to current guide dog breeding and husbandry practices is discussed.

Background: Heritability of naevi counts is widely acknowledged as a potential surveillance parameter for prevention purposes. The contribution of heritability to the changes seen in naevus number and morphology over time and their corresponding dermoscopic characteristics is unknown, but is important to understand in order to account for adequate prevention measures., Objectives: To identify naevus characteristics that are strongly influenced by heritability., Methods: This cross-sectional study included 220 individuals [76 monozygotic (MZ), 144 dizygotic (DZ)], recruited from the Brisbane Twin Naevus Study. Participants received full body imaging and dermoscopy of naevi ≥ 5 mm in diameter. Dermoscopic type, total naevus count (TNC), change in TNC with age, and naevus distribution, size, colour and profile were compared between MZ and DZ twins. Heritability of these traits was assessed via Falconer's estimate., Results: Significant differences were found in comparing MZ and DZ twins for TNC, numbers of naevi 5·0-7·9 mm in diameter, counts of light-brown naevi, naevi on the back and sun-protected sites, and naevi with the 'nonspecific' dermoscopic pattern., Conclusions: This study strongly supports a heritable component to TNC, as well as changes in TNC, and the number of medium-sized naevi, light-brown naevi, specific sites and certain dermoscopic features in adults. These characteristics should be taken into account by naevus surveillance programmes and further studied to identify candidate gene associations for clinical and dermoscopic patterns in conjunction with melanoma risk stratification., (© 2015 British Association of Dermatologists.)

Head motion (HM) is a well known confound in analyses of functional MRI (fMRI) data. Neuroimaging researchers therefore typically treat HM as a nuisance covariate in their analyses. Even so, it is possible that HM shares a common genetic influence with the trait of interest. Here we investigate the extent to which this relationship is due to shared genetic factors, using HM extracted from resting-state fMRI and maternal and self report measures of Inattention and Hyperactivity-Impulsivity from the Strengths and Weaknesses of ADHD Symptoms and Normal Behaviour (SWAN) scales. Our sample consisted of healthy young adult twins (N = 627 (63% females) including 95 MZ and 144 DZ twin pairs, mean age 22, who had mother-reported SWAN; N = 725 (58% females) including 101 MZ and 156 DZ pairs, mean age 25, with self reported SWAN). This design enabled us to distinguish genetic from environmental factors in the association between head movement and ADHD scales. HM was moderately correlated with maternal reports of Inattention (r = 0.17, p-value = 7.4E-5) and Hyperactivity-Impulsivity (r = 0.16, p-value = 2.9E-4), and these associations were mainly due to pleiotropic genetic factors with genetic correlations [95% CIs] of rg = 0.24 [0.02, 0.43] and rg = 0.23 [0.07, 0.39]. Correlations between self-reports and HM were not significant, due largely to increased measurement error. These results indicate that treating HM as a nuisance covariate in neuroimaging studies of ADHD will likely reduce power to detect between-group effects, as the implicit assumption of independence between HM and Inattention or Hyperactivity-Impulsivity is not warranted. The implications of this finding are problematic for fMRI studies of ADHD, as failing to apply HM correction is known to increase the likelihood of false positives. We discuss two ways to circumvent this problem: censoring the motion contaminated frames of the RS-fMRI scan or explicitly modeling the relationship between HM and Inattention or Hyperactivity-Impulsivity.

The aim of this study was to determine the age at onset of psoriasis in a population-based twin sample. Questionnaire-data in 10,725 twin pairs, 20-71 years of age, from the Danish Twin Registry, was collected, and analysed using survival regression analysis. Median age at onset was 25 and 28 years among women and men, respectively. The correlation between the ages was 0.84 (bootstrap standard error?=?0.044) in monozygotic twin pairs and 0.60 (0.051) in dizygotic twin pairs, permutation p?=?0.001. Age at onset of psoriasis in the index twin did not predict risk of psoriasis in the co-twin, hazard ratio (per year of later onset =?1.01 (0.99-1.03), p?=?0.434. In conclusion, these data support that the age at onset of psoriasis is, in part, an inherited property. Our results do not support that early-onset psoriasis is more genetically determined.

Purpose: Primary lens luxation (PLL) in dogs is an inherited disease in which the lens is displaced from its normal position. A truncating mutation in the ADAMTS17 orthologue on CFA03 is reported to cause PLL in several breeds, mostly terriers. However, the complex inheritance pattern of PLL in miniature bull terriers (MBTs) suggests that other loci may have a modifying effect on the ADAMTS17 mutation. This study aimed to detect such loci increasing risk of PLL in Australian MBTs., Methods: More than 170,000 single-nucleotide polymorphisms (SNPs) across the canine genome were genotyped in 23 PLL-affected and 73 normal Australian MBTs, and association between the PLL phenotype and the genetic markers was investigated by using general mixed effects Cox model survival analysis., Results: The highest association peaks, other than that associated with the ADAMTS17 mutation (P = 2.2e-05), were SNP BICF2G630420272 located at 62.2 Mb on chromosome 15 (P = 7.8e-05) and the region between 30 Mb and 32.5 Mb on chromosome 1 (P = 9.3e-05). Joint analysis showed that the PLL-associated allele of the BICF2G630420272 SNP increased risk of PLL in the presence of the ADAMTS17 mutation (P = 8.117e-04). Candidate genes in the two regions of interest included CPE on chromosome 15 and CTGF on chromosome 1. The ADAMTS17 mutation was also associated with abnormal foot and nail shapes, pedal hyperkeratosis, and persistent pupillary membranes., Conclusions: Two loci with potentially enhancing effects on the ADAMTS17 mutation were associated with PLL in Australian MBTs. Association of the ADAMTS17 mutation with possible pedal skeletal abnormalities in MBTs supports PLL in this breed and Weill-Marchesani syndrome-like disease in humans as being homologous diseases.

Eczema often precedes the development of asthma in a disease course called the 'atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10(-8)) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10(-9)). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.

Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10(-8)), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.

In the International Visible Trait Genetics (VisiGen) Consortium, we investigated the genetics of human skin color by combining a series of genome-wide association studies (GWAS) in a total of 17,262 Europeans with functional follow-up of discovered loci. Our GWAS provide the first genome-wide significant evidence for chromosome 20q11.22 harboring the ASIP gene being explicitly associated with skin color in Europeans. In addition, genomic loci at 5p13.2 (SLC45A2), 6p25.3 (IRF4), 15q13.1 (HERC2/OCA2), and 16q24.3 (MC1R) were confirmed to be involved in skin coloration in Europeans. In follow-up gene expression and regulation studies of 22 genes in 20q11.22, we highlighted two novel genes EIF2S2 and GSS, serving as competing functional candidates in this region and providing future research lines. A genetically inferred skin color score obtained from the 9 top-associated SNPs from 9 genes in 940 worldwide samples (HGDP-CEPH) showed a clear gradual pattern in Western Eurasians similar to the distribution of physical skin color, suggesting the used 9 SNPs as suitable markers for DNA prediction of skin color in Europeans and neighboring populations, relevant in future forensic and anthropological investigations.

Abuse is an intentional act that causes harm to an individual. Dogs (Canis familiaris) with a known or suspected history of abuse were solicited for the study. A panel of 5 experts in canine behavior and abuse selected the dogs judged as having a certain or near certain history of being abused for inclusion in the study. Behavioral evaluations of the dogs were obtained using the Canine Behavioral Assessment and Research Questionnaire, which utilizes ordinal scales to rate either the intensity or frequency of the dog's behaviors. Sixty-nine dogs ultimately met the criteria for inclusion in the study. When compared with a convenience sample of 5,239 companion dogs, abused dogs were reported as displaying significantly higher rates of aggression and fear directed toward unfamiliar humans and dogs, excitability, hyperactivity, attachment and attention-seeking behaviors, persistent barking, and miscellaneous strange or repetitive behaviors. Delineating the behavioral and psychological characteristics of abused dogs provides the first step in identifying and distinguishing the risk factors and sequelae associated with abuse, which may inform the development of preventive and therapeutic programs for nonhuman animal abuse.

The heritability of attention-deficit/hyperactivity disorder (ADHD) is higher for children than adults. This may be due to increasing importance of environment in symptom variation, measurement inaccuracy when two raters report behavior of a twin-pair, a contrast effect resulting from parental comparison of siblings and/or dimensionality of measures. We examine rater contrast and sex effects in ADHD subtypes using a dimensional scale and compare the aetiology of self, versus maternal-report. Data were collected using the Strengths and Weaknesses of ADHD and Normal Behaviour Scale (SWAN): maternal-report for 3,223 twins and siblings (mean age 21.2, SD = 6.3) and self-report for 1,617 twins and siblings (mean age 25.5, SD = 3.2). Contrast effects and magnitude of genetic and environmental contributions to variance of ADHD phenotypes (inattention, hyperactivity-impulsivity, combined behaviours) were examined using structural equation modeling. Contrast effects were evident for maternal-report hyperactivity-impulsivity (b = -0.04) and self-report inattention (-0.09) and combined ADHD (-0.08). Dominant genetic effects were shared by raters for inattention, hyperactivity-impulsivity and combined ADHD. Broad-sense heritability was equal across sex for maternal-report inattention, hyperactivity-impulsivity and combined ADHD (0.72, 0.83, 0.80). Heritability for corresponding subtypes in self-reported data were best represented by sex (0.46, 0.30, 0.39 for males; 0.69, 0.41, 0.65 for females). Heritability difference between maternal and self-report ADHD was due to greater variance of male specific environment in self-report data. Self-reported ADHD differed across sex by magnitude of specific environment and genetic effects.

The goal of the present study was to evaluate a shortened, 42-item version of the Canine Behavioral Assessment and Research Questionnaire (C-BARQ((S))) as a behavioral screening tool for dogs relinquished to animal shelters. In contrast to a previous finding, the current study found no consistent evidence that relinquishing owners gave unreliable or biased responses to the questionnaire depending on whether or not they believed that this information would be shared with shelter staff or used to evaluate dogs for adoption. Relinquishing owners' C-BARQ((S)) responses for items related to aggression and fear directed toward humans and other dogs correlated with independent subjective assessments of aggressiveness made by shelter staff (generalized linear mixed models, P<0.05, N=84 aggressive dogs, N=156 non-aggressive dogs). In addition, C-BARQ((S)) scores successfully discriminated between dogs based on their eventual outcomes (i.e., adoption or euthanasia; Generalized Linear Mixed Models, P<0.05, N=181 adopted, N=177 euthanized), indicating convergent validity. Follow-up surveys with a subset of adoptive owners (N=53) revealed significant correlations (after correction for multiple comparisons) between relinquishing and adoptive owners' C-BARQ((S)) ratings for 3 behavioral traits: stranger-directed aggression (rs=0.494, P<0.001), chewing inappropriate objects (rs=0.402, P<0.01), and urination when left alone (rs=0.421, P<0.01). Overall, the findings confirmed the value of this type of shelter intake survey instrument for screening owner-surrendered dogs for the presence of behavior problems., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Prevention strategies that delay the onset of asthma may improve clinical outcomes. To identify early life environmental exposures associated with asthma age-of-onset and potential genetic modifiers of these exposures, we studied 1085 subjects with physician-diagnosed asthma and disease onset at or after age two. Subjects reported retrospectively on their exposure to 17 environmental factors before the age of two. The presence of individual or combinations of these early life exposures was then tested for association with variation in asthma age-of-onset. For exposures significantly associated with age-of-onset, we tested if 26 single nucleotide polymorphisms (SNP) with an established association with allergic disease significantly modified the effect of the exposure. Five environmental exposures were significantly associated with variation in asthma age-of-onset after correction for multiple testing: carpet at home (P = 6 × 10(-5)), a serious chest illness (P = 10(-4)), father a cigarette smoker (P = 6 × 10(-4)) and direct exposure to father's smoking (P = 3 × 10(-4)). Individuals with early childhood asthma onset, between the ages of two and six, were 1.4-fold (CI 1.1-1.9) more likely to report having lived in a house with carpet and 2.1-fold (CI 1.3-3.5) more likely to report suffering a serious chest illness before the age of two, than asthmatics with later disease onset. We further found these individual risks to increase to 3.2-fold (CI 1.7-6.0) if carpet exposure and suffering a serious chest illness co-occurred before age two. Paternal smoking exposures were less likely to be reported by asthmatics with early when compared to later disease onset (OR 0.5, CI 0.3-0.7). There were no significant SNP interactions with these environmental exposures after correction for multiple testing. Our results suggest that disease onset in individuals at a high-risk of developing asthma can potentially be delayed by avoiding exposure to carpet at home and preventing serious chest illnesses during the first 2 years of life.

Although genetic studies have reported a number of loci associated with melanoma risk, the complex genetic architecture of the disease is not yet fully understood. We sought to identify common genetic variants associated with melanoma risk in a genome-wide association study (GWAS) of 2298 cases and 6654 controls. Thirteen of 15 known loci were replicated with nominal significance. A total of 69 single-nucleotide polymorphisms (SNPs) were selected for in silico replication in two independent melanoma GWAS datasets (a total of 5149 cases and 12 795 controls). Seven novel loci were nominally significantly associated with melanoma risk. These seven SNPs were further genotyped in 234 melanoma cases and 238 controls. The SNP rs4698934 was nominally significantly associated with melanoma risk. The combined odds ratio per T allele = 1.18; 95% confidence interval (1.10-1.25); combined P = 7.70 × 10(-) (7). This SNP is located in the intron of the TET2 gene on chromosome 4q24. In addition, a novel somatic mutation of TET2 was identified by next-generation sequencing in 1 of 22 sporadic melanoma cases. TET2 encodes a member of TET family enzymes that oxidizes 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). It is a putative epigenetic biomarker of melanoma as we previously reported, with observation of reduced TET2 transcriptional expression. This study is the first to implicate TET2 genetic variation and mutation in melanoma., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

We have compared the melanogenic activities of cultured melanocytes carrying two common TYR alleles as homozygous 192S-402R wild-type, heterozygous and homozygous variant. This includes assays of TYR protein, DOPAoxidase activity, glycosylation and temperature sensitivity of protein and DOPAoxidase levels. Homozygous wild-type strains on average had higher levels of TYR protein and enzyme activity than other genotypes. Homozygous 402Q/Q melanocytes produced significantly less TYR protein, displayed altered trafficking and glycosylation, with reduced DOPAoxidase. However, near wild-type TYR activity levels could be recovered at lower growth temperature. In a sample population from Southeast Queensland, these two polymorphisms were present on four TYR haplotypes, designated as WT 192S-402R, 192Y-402R and 192S-402Q with a double-variant 192Y-402Q of low frequency at 1.9%. Based on cell culture findings and haplotype associations, we have used an additive model to assess the penetrance of the ten possible TYR genotypes derived from the combination of these haplotypes., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever., Objective: We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases., Methods: We performed a meta-analysis of GWASs comparing persons with both physician-diagnosed asthma and hay fever (n = 6,685) with persons with neither disease (n = 14,091)., Results: At genome-wide significance, we identified 11 independent variants associated with the risk of having asthma with hay fever, including 2 associations reaching this level of significance with allergic disease for the first time: ZBTB10 (rs7009110; odds ratio [OR], 1.14; P = 4 × 10(-9)) and CLEC16A (rs62026376; OR, 1.17; P = 1 × 10(-8)). The rs62026376:C allele associated with increased asthma with hay fever risk has been found to be associated also with decreased expression of the nearby DEXI gene in monocytes. The 11 variants were associated with the risk of asthma and hay fever separately, but the estimated associations with the individual phenotypes were weaker than with the combined asthma with hay fever phenotype. A variant near LRRC32 was a stronger risk factor for hay fever than for asthma, whereas the reverse was observed for variants in/near GSDMA and TSLP. Single nucleotide polymorphisms with suggestive evidence for association with asthma with hay fever risk included rs41295115 near IL2RA (OR, 1.28; P = 5 × 10(-7)) and rs76043829 in TNS1 (OR, 1.23; P = 2 × 10(-6))., Conclusion: By focusing on the combined phenotype of asthma with hay fever, variants associated with the risk of allergic disease can be identified with greater efficiency., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Objectives: To determine the heritability of extra-hepatic portosystemic shunts and elevated post-prandial serum bile acid concentrations in Maltese dogs., Materials and Methods: Maltese dogs were recruited and investigated by a variable combination of procedures including dynamic bile acid testing, rectal ammonia tolerance testing, ultrasonography, portal venography, surgical inspection or necropsy. In addition, nine test matings were carried out between affected and affected dogs, and affected and unaffected dogs., Results: In 135 variably related Maltese, shunt status could be confirmed in 113, including 19 with an extra-hepatic portosystemic shunt (17 confirmed at surgery, 2 at necropsy). Rectal ammonia tolerance testing results and post-prandial serum bile acid concentrations were retrievable for 50 and 88 dogs, respectively. Pedigree information was available for these 135 and an additional 164 related dogs. Two consecutive test matings were carried out between two affected animals (whose shunts had been attenuated), with 2 of 8 (25%) of offspring having an extra-hepatic portosystemic shunt. Six test matings were carried out between an affected and an unaffected animal, with 2 of 22 (9%) offspring affected. Heritability of extra-hepatic portosystemic shunt was 0·61 calculated using variance components analysis [95% confidence interval (CI) 0·14 to 1·0, P=0·001]. The best fitting model from segregation analysis was a common, partially penetrant, recessive model (allele frequency 0·34, penetrance 0·99, CI 0·09 to 1·0). The heritability of elevated post-prandial serum bile acid (and thus likely portal vein hypoplasia) was 0·81 (CI 0·43 to 1·0, P=0·2) after logarithmic transformation of post-prandial serum bile acid concentrations., Clinical Significance: There is strong support for extra-hepatic portosystemic shunts and elevated post-prandial serum bile acid concentrations both being inherited conditions in Maltese., (© 2013 British Small Animal Veterinary Association.)

Dogs offer unique opportunities to study correlations between morphology and behavior because skull shapes and body shape are so diverse among breeds. Several studies have shown relationships between canine cephalic index (CI: the ratio of skull width to skull length) and neural architecture. Data on the CI of adult, show-quality dogs (six males and six females) were sourced in Australia along with existing data on the breeds' height, bodyweight and related to data on 36 behavioral traits of companion dogs (n = 8,301) of various common breeds (n = 49) collected internationally using the Canine Behavioral Assessment and Research Questionnaire (C-BARQ). Stepwise backward elimination regressions revealed that, across the breeds, 33 behavioral traits all but one of which are undesirable in companion animals correlated with either height alone (n = 14), bodyweight alone (n = 5), CI alone (n = 3), bodyweight-and-skull shape combined (n = 2), height-and-skull shape combined (n = 3) or height-and-bodyweight combined (n = 6). For example, breed average height showed strongly significant inverse relationships (p<0.001) with mounting persons or objects, touch sensitivity, urination when left alone, dog-directed fear, separation-related problems, non-social fear, defecation when left alone, owner-directed aggression, begging for food, urine marking and attachment/attention-seeking, while bodyweight showed strongly significant inverse relationships (p<0.001) with excitability and being reported as hyperactive. Apart from trainability, all regression coefficients with height were negative indicating that, across the breeds, behavior becomes more problematic as height decreases. Allogrooming increased strongly (p<0.001) with CI and inversely with height. CI alone showed a strong significant positive relationship with self-grooming (p<0.001) but a negative relationship with chasing (p = 0.020). The current study demonstrates how aspects of CI (and therefore brain shape), bodyweight and height co-vary with behavior. The biological basis for, and significance of, these associations remain to be determined.

The main genetic determinant of soluble interleukin 6 receptor (sIL-6R) levels is the missense variant rs2228145 that maps to the cleavage site of IL-6R. For each Ala allele, sIL-6R serum levels increase by ≈ 20 ng ml(-1) and asthma risk by 1.09-fold. However, this variant does not explain the total heritability for sIL-6R levels. Additional independent variants in IL6R may therefore contribute to variation in sIL-6R levels and influence asthma risk. We imputed 471 variants in IL6R and tested these for association with sIL-6R serum levels in 360 individuals. An intronic variant (rs12083537) was associated with sIL-6R levels independently of rs4129267 (P=0.0005), a proxy single-nucleotide polymorphism for rs2228145. A significant and consistent association for rs12083537 was observed in a replication panel of 354 individuals (P=0.033). Each rs12083537:A allele increased sIL-6R serum levels by 2.4 ng ml(-1). Analysis of mRNA levels in two cohorts did not identify significant associations between rs12083537 and IL6R transcription levels. On the other hand, results from 16,705 asthmatics and 30,809 controls showed that the rs12083537:A allele increased asthma risk by 1.04-fold (P=0.0419). Genetic risk scores based on IL6R regulatory variants may prove useful in explaining variation in clinical response to tocilizumab, an anti-IL-6R monoclonal antibody.

Allergen-specific immunoglobulin E (present in allergic sensitization) has a central role in the pathogenesis of allergic disease. We performed the first large-scale genome-wide association study (GWAS) of allergic sensitization in 5,789 affected individuals and 10,056 controls and followed up the top SNP at each of 26 loci in 6,114 affected individuals and 9,920 controls. We increased the number of susceptibility loci with genome-wide significant association with allergic sensitization from three to ten, including SNPs in or near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL2 and HLA-B. All the top SNPs were associated with allergic symptoms in an independent study. Risk-associated variants at these ten loci were estimated to account for at least 25% of allergic sensitization and allergic rhinitis. Understanding the molecular mechanisms underlying these associations may provide new insights into the etiology of allergic disease.

Objective: To compare the owner-reported prevalence of behavioral characteristics in dogs obtained as puppies from pet stores with that of dogs obtained as puppies from noncommercial breeders., Design: Cross-sectional study. Animals-Dogs obtained as puppies from pet stores (n = 413) and breeder-obtained dogs (5,657)., Procedures: Behavioral evaluations were obtained from a large convenience sample of current dog owners with the online version of the Canine Behavioral Assessment and Research Questionnaire, which uses ordinal scales to rate either the intensity or frequency of the dogs' behavior. Hierarchic linear and logistic regression models were used to analyze the effects of source of acquisition on behavioral outcomes when various confounding and intervening variables were controlled for., Results: Pet store-derived dogs received significantly less favorable scores than did breeder-obtained dogs on 12 of 14 of the behavioral variables measured; pet store dogs did not score more favorably than breeder dogs in any behavioral category. Compared with dogs obtained as puppies from noncommercial breeders, dogs obtained as puppies from pet stores had significantly greater aggression toward human family members, unfamiliar people, and other dogs; greater fear of other dogs and nonsocial stimuli; and greater separation-related problems and house soiling., Conclusions and Clinical Relevance: Obtaining dogs from pet stores versus noncommercial breeders represented a significant risk factor for the development of a wide range of undesirable behavioral characteristics. Until the causes of the unfavorable differences detected in this group of dogs can be specifically identified and remedied, the authors cannot recommend that puppies be obtained from pet stores.

When a forensic DNA sample cannot be associated directly with a previously genotyped reference sample by standard short tandem repeat profiling, the investigation required for identifying perpetrators, victims, or missing persons can be both costly and time consuming. Here, we describe the outcome of a collaborative study using the Identitas Version 1 (v1) Forensic Chip, the first commercially available all-in-one tool dedicated to the concept of developing intelligence leads based on DNA. The chip allows parallel interrogation of 201,173 genome-wide autosomal, X-chromosomal, Y-chromosomal, and mitochondrial single nucleotide polymorphisms for inference of biogeographic ancestry, appearance, relatedness, and sex. The first assessment of the chip's performance was carried out on 3,196 blinded DNA samples of varying quantities and qualities, covering a wide range of biogeographic origin and eye/hair coloration as well as variation in relatedness and sex. Overall, 95 % of the samples (N = 3,034) passed quality checks with an overall genotype call rate >90 % on variable numbers of available recorded trait information. Predictions of sex, direct match, and first to third degree relatedness were highly accurate. Chip-based predictions of biparental continental ancestry were on average ~94 % correct (further support provided by separately inferred patrilineal and matrilineal ancestry). Predictions of eye color were 85 % correct for brown and 70 % correct for blue eyes, and predictions of hair color were 72 % for brown, 63 % for blond, 58 % for black, and 48 % for red hair. From the 5 % of samples (N = 162) with <90 % call rate, 56 % yielded correct continental ancestry predictions while 7 % yielded sufficient genotypes to allow hair and eye color prediction. Our results demonstrate that the Identitas v1 Forensic Chip holds great promise for a wide range of applications including criminal investigations, missing person investigations, and for national security purposes.

Genome-wide association studies (GWAS) of attention-deficit/hyperactivity disorder (ADHD) offer the benefit of a hypothesis-free approach to measuring the quantitative effect of genetic variants on affection status. Generally the findings of GWAS relying on ADHD status have been non-significant, but the one study using quantitative measures of symptoms found SLC9A9 and SLC6A1 were associated with inattention and hyperactivity-impulsivity. Accordingly, we performed a GWAS using quantitative measures of each ADHD subtype measured with the Strengths and Weaknesses of ADHD and Normal Behaviour (SWAN) scale in two community-based samples. This scale captures the full range of attention and kinetic behavior; from high levels of attention and appropriate activity to the inattention and hyperactivity-impulsivity associated with ADHD within two community-based samples. Our discovery sample comprised 1,851 participants (mean age = 22.8 years [4.8]; 50.6% female), while our replication sample comprised 155 participants (mean age = 26.3 years [3.1]; 68.4% females). Age, sex, age × sex, and age2 were included as covariates and the results from each sample were combined using meta-analysis, then analyzed with a gene-based test to estimate the combined effect of markers within genes. We compare our results with markers that have previously been found to have a strong association with ADHD symptoms. Neither the GWAS nor subsequent meta-analyses yielded genome-wide significant results; the strongest effect was observed at rs2110267 (4.62 × 10-7) for symptoms of hyperactivity-impulsivity. The strongest effect in the gene-based test was for GPR139 on symptoms of inattention (6.40 × 10-5). Replication of this study with larger samples will add to our understanding of the genetic etiology of ADHD.

[This corrects the article DOI: 10.1371/journal.pone.0044008.].

Genome-wide association studies and comparative genomics have established major loci and specific polymorphisms affecting human skin, hair and eye color. Environmental changes have had an impact on selected pigmentation genes as populations have expanded into different regions of the globe.

Canine atopic dermatitis (AD) is an allergic inflammatory skin disease that shares similarities with AD in humans. Canine AD is likely to be an inherited disease in dogs and is common in West Highland white terriers (WHWTs). We performed a genome-wide association study using the Affymetrix Canine SNP V2 array consisting of over 42,800 single nucleotide polymorphisms, on 35 atopic and 25 non-atopic WHWTs. A gene-dropping simulation method, using SIB-PAIR, identified a projected 1.3 Mb area of association (genome-wide P = 6 × 10(-5) to P = 7 × 10(-4)) on CFA 17. Nineteen genes on CFA 17, including 1 potential candidate gene (PTPN22), were located less than 0.5 Mb from the interval of association identified on the genome-wide association analysis. Four haplotypes within this locus were differently distributed between cases and controls in this population of dogs. These findings suggest that a major locus for canine AD in WHWTs may be located on, or in close proximity to an area on CFA 17.

Background: The Prevalence and persistence of ADHD have not been described in young Australian adults and few studies have examined how conduct problems (CP) are associated with ADHD for this age group. We estimate lifetime and adult prevalence and persistence rates for three categories of ADHD for 3795 Australian adults, and indicate how career, health and childhood risk factors differ for people with ADHD symptoms and ADHD symptoms plus CP., Methodology: Trained interviewers collected participant experience of ADHD, CP, education, employment, childhood experience, relationship and health variables. Three diagnostic definitions of ADHD used were (i) full DSM-IV criteria; (ii) excluding the age 7 onset criterion (no age criterion); (iii) participant experienced difficulties due to ADHD symptoms (problem symptoms)., Results: Prevalence rates in adulthood were 1.1%, 2.3% and 2.7% for each categorization respectively. Persistence of ADHD from childhood averaged across gender was 55.3% for full criteria, 50.3% with no age criterion and 40.2% for problem symptoms. ADHD symptoms were associated with parental conflict, poor health, being sexually assaulted during childhood, lower education, income loss and higher unemployment. The lifetime prevalence of conduct problems for adults with ADHD was 57.8% and 6.9% for adults without ADHD. The greatest disadvantage was experienced by participants with ADHD plus CP., Conclusion: The persistence of ADHD into adulthood was greatest for participants meeting full diagnostic criteria and inattention was associated with the greatest loss of income and disadvantage. The disadvantage associated with conduct problems differed in severity and was relevant for a high proportion of adults with ADHD. Women but not men with ADHD reported more childhood adversity, possibly indicating varied etiology and treatment needs. The impact and treatment needs of adults with ADHD and CP and the report of sexual assault during childhood by women and men with ADHD also deserve further study.

Rationale: Asthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies., Objectives: To test if population-based cohorts with self-reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations., Methods: The APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P<5 x 10(-8)) and three variants reported as suggestive (P<5× 10(-7)). We also searched for novel associations in APCAT (Stage 1) and followed-up the most promising variants in 4,035 asthmatics and 11,251 healthy controls (Stage 2). Finally, we conducted the first genome-wide screen for interactions with smoking or hay fever., Main Results: We observed association in the same direction for all thirteen previously reported variants and nominally replicated ten of them. One variant that was previously suggestive, rs11071559 in RORA, now reaches genome-wide significance when combined with our data (P = 2.4 × 10(-9)). We also identified two genome-wide significant associations: rs13408661 near IL1RL1/IL18R1 (P(Stage1+Stage2) = 1.1x10(-9)), which is correlated with a variant recently shown to be associated with asthma (rs3771180), and rs9268516 in the HLA region (P(Stage1+Stage2) = 1.1x10(-8)), which appears to be independent of previously reported associations in this locus. Finally, we found no strong evidence for gene-environment interactions with smoking or hay fever status., Conclusions: Population-based cohorts with simple asthma phenotypes represent a valuable and largely untapped resource for genetic studies of asthma.

Background: Canine atopic dermatitis is an allergic inflammatory skin disease common in West Highland white terriers. A genome-wide association study for atopic dermatitis in a population of West Highland white terriers identified a 1.3 Mb area of association on CFA17 containing canine protein tyrosine phosphatase non-receptor type 22 (lymphoid) PTPN22. This gene is a potential candidate gene for canine atopic dermatitis as it encodes a lymphoid-specific signalling mediator that regulates T-cell and possibly B-cell activity., Findings: Sequencing of PTPN22 in three atopic and three non-atopic West Highland white terriers identified 18 polymorphisms, including five genetic variants with a bioinformatically predicted functional effect. An intronic polymorphic repeat sequence variant was excluded as the cause of the genome-wide association study peak signal, by large-scale genotyping in 72 West Highland white terriers (gene-dropping simulation method, P = 0.01)., Conclusions: This study identified 18 genetic variants in PTPN22 that might be associated with atopic dermatitis in West Highland white terriers. This preliminary data may direct further study on the role of PTPN22 in this disease. Large scale genotyping and complementary genomic and proteomic assays would be required to assess this possibility.

Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10(-13)) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10(-9)), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10(-8)). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis.

Background: Canine atopic dermatitis (AD) is a common inflammatory skin disease associated with defects in the epidermal barrier, particularly in West Highland white terriers (WHWTs). It shares many similarities with human AD, and so may be a useful animal model for this disease. Epidermal dysfunction in human AD can be caused by mutations in the gene encoding the epidermal protein filaggrin (FLG) and, in some atopic patients, be associated with altered FLG mRNA and protein expression in lesional and/or non-lesional skin. In experimental models of canine AD, mRNA expression of the orthologous canine filaggrin gene may be reduced in non-lesional skin compared with healthy controls. However, there is no published data on canine filaggrin mRNA expression in the skin of dogs with naturally-occurring AD. Hence, the aim of this pilot study was to develop a reverse transcriptase real-time PCR assay to compare filaggrin mRNA expression in the skin of atopic (n = 7) and non-atopic dogs (n = 5) from five breeds, including eight WHWTs., Findings: Overall, filaggrin mRNA expression in non-lesional atopic skin was decreased compared to non-lesional non-atopic skin (two fold change); however this difference was only statistically significant in the subgroup of WHWTs (P = 0.03)., Conclusions: Although limited by the small sample size, these results indicate that, comparable to some cases of human AD, altered filaggrin mRNA expression may exist in the skin of some atopic dogs with naturally-occurring disease. Additional studies, including larger sample numbers, will be necessary to confirm this finding and to investigate whether mutations in the filaggrin gene exist and contribute to epidermal lesions of AD in dogs.

So far, two genes associated with familial melanoma have been identified, accounting for a minority of genetic risk in families. Mutations in CDKN2A account for approximately 40% of familial cases, and predisposing mutations in CDK4 have been reported in a very small number of melanoma kindreds. Here we report the whole-genome sequencing of probands from several melanoma families, which we performed in order to identify other genes associated with familial melanoma. We identify one individual carrying a novel germline variant (coding DNA sequence c.G1075A; protein sequence p.E318K; rs149617956) in the melanoma-lineage-specific oncogene microphthalmia-associated transcription factor (MITF). Although the variant co-segregated with melanoma in some but not all cases in the family, linkage analysis of 31 families subsequently identified to carry the variant generated a log of odds (lod) score of 2.7 under a dominant model, indicating E318K as a possible intermediate risk variant. Consistent with this, the E318K variant was significantly associated with melanoma in a large Australian case-control sample. Likewise, it was similarly associated in an independent case-control sample from the United Kingdom. In the Australian sample, the variant allele was significantly over-represented in cases with a family history of melanoma, multiple primary melanomas, or both. The variant allele was also associated with increased naevus count and non-blue eye colour. Functional analysis of E318K showed that MITF encoded by the variant allele had impaired sumoylation and differentially regulated several MITF targets. These data indicate that MITF is a melanoma-predisposition gene and highlight the utility of whole-genome sequencing to identify novel rare variants associated with disease susceptibility.

We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP-CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 × 10(-11), OR in combined replication cohorts of 0.89 (95% CI 0.85-0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 × 10(-8)). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density.

An evolving hypothesis postulates that melanomas may arise through 'nevus-associated' and 'chronic sun exposure' pathways. We explored this hypothesis by examining associations between nevus-associated loci and melanoma risk across strata of body site and histological subtype. We genotyped 1028 invasive case patients and 1469 controls for variants in methylthioadenosine phosphorylase (MTAP), phospholipase A2, group VI (PLA2G6), and Interferon regulatory factor 4 (IRF4), and compared allelic frequencies globally and by anatomical site and histological subtype of melanoma. Odds-ratios (ORs) and 95% confidence intervals (CIs) were calculated using classical and multinomial logistic regression models. Among controls, MTAP rs10757257, PLA2G6 rs132985 and IRF4 rs12203592 were the variants most significantly associated with number of nevi. In adjusted models, a significant association was found between MTAP rs10757257 and overall melanoma risk (OR = 1.32, 95% CI = 1.14-1.53), with no evidence of heterogeneity across sites (Phomogeneity =.52). In contrast, MTAP rs10757257 was associated with superficial spreading/nodular melanoma (OR = 1.34, 95% CI = 1.15- 1.57), but not with lentigo maligna melanoma (OR = 0.79, 95% CI = 0.46-1.35) (Phomogeneity =.06), the subtype associated with chronic sun exposure. Melanoma was significantly inversely associated with rs12203592 in children (OR = 0.35, 95% CI = 0.16-0.77) and adolescents (OR = 0.61, 95% CI = 0.42-0.91), but not in adults (Phomogeneity =.0008). Our results suggest that the relationship between MTAP and melanoma is subtype-specific, and that the association between IRF4 and melanoma is more evident for cases with a younger age at onset. These findings lend some support to the 'divergent pathways' hypothesis and may provide at least one candidate gene underlying this model. Further studies are warranted to confirm these findings and improve our understanding of these relationships.

Genes in the TGF9 signaling pathway play important roles in the regulation of ovarian follicle growth and ovulation rate. Mutations in three genes in this pathway, growth differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15) and the bone morphogenetic protein receptor B 1 (BMPRB1), influence dizygotic (DZ) twinning rates in sheep. To date, only variants in GDF9 and BMP15, but not their receptors transforming growth factor ß receptor 1 (TGFBR1), bone morphogenetic protein receptor 2 (BMPR2) and BMPR1B, have been investigated with respect to their roles in human DZ twinning. We screened for rare and novel variants in TGFBR1, BMPR2 and BMPR1B in mothers of dizygotic twins (MODZT) from twin-dense families, and assessed association between genotyped and imputed variants and DZ twinning in another large sample of MODZT. Three novel variants were found: a deep intronic variant in BMPR2, and one intronic and one non-synonymous exonic variant in BMPRB1 which would result in the replacement of glutamine by glutamic acid at amino acid position 294 (p.Gln294Glu). None of these variants were predicted to have major impacts on gene function. However, the p.Gln294Glu variant changes the same amino acid as a sheep BMPR1B functional variant and may have functional consequences. Six BMPR1B variants were marginally associated with DZ twinning in the larger case-control sample, but these were no longer significant once multiple testing was taken into account. Our results suggest that variation in the TGF9 signaling pathway type II receptors has limited effects on DZ twinning rates in humans.

Background: We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying the disease., Methods: We did a genome-wide association study (GWAS) in 2669 physician-diagnosed asthmatics and 4528 controls from Australia. Seven loci were prioritised for replication after combining our results with those from the GABRIEL consortium (n=26,475), and these were tested in an additional 25,358 independent samples from four in-silico cohorts. Quantitative multi-marker scores of genetic load were constructed on the basis of results from the GABRIEL study and tested for association with asthma in our Australian GWAS dataset., Findings: Two loci were confirmed to associate with asthma risk in the replication cohorts and reached genome-wide significance in the combined analysis of all available studies (n=57,800): rs4129267 (OR 1·09, combined p=2·4×10(-8)) in the interleukin-6 receptor (IL6R) gene and rs7130588 (OR 1·09, p=1·8×10(-8)) on chromosome 11q13.5 near the leucine-rich repeat containing 32 gene (LRRC32, also known as GARP). The 11q13.5 locus was significantly associated with atopic status among asthmatics (OR 1·33, p=7×10(-4)), suggesting that it is a risk factor for allergic but not non-allergic asthma. Multi-marker association results are consistent with a highly polygenic contribution to asthma risk, including loci with weak effects that might be shared with other immune-related diseases, such as NDFIP1, HLA-B, LPP, and BACH2., Interpretation: The IL6R association further supports the hypothesis that cytokine signalling dysregulation affects asthma risk, and raises the possibility that an IL6R antagonist (tocilizumab) may be effective to treat the disease, perhaps in a genotype-dependent manner. Results for the 11q13.5 locus suggest that it directly increases the risk of allergic sensitisation which, in turn, increases the risk of subsequent development of asthma. Larger or more functionally focused studies are needed to characterise the many loci with modest effects that remain to be identified for asthma., Funding: National Health and Medical Research Council of Australia. A full list of funding sources is provided in the webappendix., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Immunoglobulin E (IgE)-mediated hypersensitivity against environmental allergens, commonly including Dermatophagoides farinae, is associated with atopic diseases in both humans and dogs. We have recently identified a family of clinically healthy West Highland white terriers (WHWTs) with high-serum D. farinae-IgE levels. In this study, we investigated the genetic mechanism controlling IgE responsiveness in dogs by performing a genome-wide association study (GWAS) using the Affymetrix V2 Dog SNP array in 31 high-IgE and 24 low-IgE responder WHWTs. A gene-dropping simulation method, using SIB-PAIR software, showed significant allelic association between serum D. farinae-specific IgE levels and a 2.3-Mb area on CFA35 (best empirical P = 1 × 10(-5)). A nearby candidate gene, CD83, encodes a protein which has important immunological functions in antigen presentation and regulation of humoral immune responses. We sequenced this gene in 2 high-IgE responders and 2 low-IgE responders and identified an intronic polymorphic repeat sequence with a predicted functional effect, but the association was insufficient to explain the GWAS association signal in this population (P = 1 × 10(-3)). Further studies are necessary to investigate the significance of these findings for IgE responsiveness and atopic disease in the dog.

Human iris patterns are highly variable. The origins of this variation are of interest in the study of iris-related eye diseases and forensics, as well as from an embryological developmental perspective, with regard to their possible relationship to fundamental processes of neurodevelopment. We have performed genome-wide association scans on four iris characteristics (crypt frequency, furrow contractions, presence of peripupillary pigmented ring, and number of nevi) in three Australian samples of European descent. Both the discovery (n = 2121) and replication (n = 499 and 73) samples showed evidence for association between (1) crypt frequency and variants in the axonal guidance gene SEMA3A (p = 6.6 × 10(-11)), (2) furrow contractions and variants within the cytoskeleton gene TRAF3IP1 (p = 2.3 × 10(-12)), and (3) the pigmented ring and variants in the well-known pigmentation gene SLC24A4 (p = 7.6 × 10(-21)). These replicated findings individually accounted for around 1.5%-3% of the variance for these iris characteristics. Because both SEMA3A and TRAFIP1 are implicated in pathways that control neurogenesis, neural migration, and synaptogenesis, we also examined the evidence of enhancement among such genes, finding enrichment for crypts and furrows. These findings suggest that genes involved in normal neuronal pattern development may also influence tissue structures in the human iris., (Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Aim: To study the association between type 1 diabetes and atopic diseases in a twin population., Methods: We performed record linkage between questionnaire-defined atopic dermatitis, asthma and hay fever, and hospital discharge diagnoses of type 1 diabetes in 54,530 Danish twins, 3-71 years of age., Results: The age- and sex-adjusted risk of atopic dermatitis was decreased in subjects with type 1 diabetes compared with nondiabetic subjects, (2.1%vs 9.9%), odds ratio (OR)= 0.23 (0.07-0.71), P = 0.011, whereas asthma and hay fever were not significantly associated with type 1 diabetes. Within twin pairs discordant for type 1 diabetes, the diabetic twin had a lower risk of atopic dermatitis relative to the nondiabetic co-twin. Genetic factors for atopic dermatitis and type 1 diabetes were negatively correlated (r = -0.30), P = 0.0009., Conclusions: These findings substantiate the Th1 vs Th2 cell dichotomy for type 1 diabetes and atopic dermatitis, and indicate an inverse association between genetic factors for these disorders., (© 2010 John Wiley & Sons A/S.)

Aim: To examine the relationship between asthma, type 2 diabetes and increased body mass index (BMI) in adult twins., Methods: We performed record linkage between questionnaire-defined asthma and BMI, and hospital discharge diagnoses of type 2 diabetes in 34,782 Danish twins, 20-71 years of age., Results: The risk of asthma was increased in subjects with type 2 diabetes relative to nondiabetic subjects both in men (13.5%vs 7.5%), P = 0.001 and in women (16.6%vs 9.6%), P = 0.001. The result remained significant after adjustment for age, BMI, smoking, symptoms of chronic bronchitis, marital status and zygosity, men: OR = 1.70 (1.07-2.70), P = 0.026; women: OR = 1.88 (1.24-2.85), P = 0.003. In this analysis, BMI remained a highly significant predictor for asthma independently of diabetes status in women, P < 0.000 but not in men, P = 0.336. Significant positive genetic correlations were found between asthma and type 2 diabetes, 0.20 (0.01-0.40), P = 0.047; between asthma and BMI in women, 0.15 (0.07-0.22), P < 0.000; and between BMI and type 2 diabetes, 0.40 (0.29-0.43), P < 0.000., Conclusions: Asthma, type 2 diabetes and increased BMI are strongly associated in adults, particularly in women. These results suggest a common aetiology for asthma and metabolic syndrome., (© 2010 John Wiley & Sons A/S.)

Genome-wide association studies followed by replication provide a powerful approach to map genetic risk factors for asthma. We sought to search for new variants associated with asthma and attempt to replicate the association with four loci reported previously (ORMDL3, PDE4D, DENND1B and IL1RL1). Genome-wide association analyses of individual single nucleotide polymorphisms (SNPs), rare copy number variants (CNVs) and overall CNV burden were carried out in 986 asthma cases and 1846 asthma-free controls from Australia. The most-associated locus in the SNP analysis was ORMDL3 (rs6503525, P = 4.8 × 10⁻⁷). Five other loci were associated with P < 10⁻⁵, most notably the chemokine CXC motif ligand 14 (CXCL14) gene (rs31263, P = 7.8 × 10⁻⁶). We found no evidence for association with the specific risk variants reported recently for PDE4D, DENND1B and ILR1L1. However, a variant in IL1RL1 that is in low linkage disequilibrium with that reported previously was associated with asthma risk after accounting for all variants tested (rs10197862, gene wide P = 0.01). This association replicated convincingly in an independent cohort (P = 2.4 × 10⁻⁴). A 300-kb deletion on chromosome 17q21 was associated with asthma risk, but this did not reach experiment-wide significance. Asthma cases and controls had comparable CNV rates, length and number of genes affected by deletions or duplications. In conclusion, we confirm the association between asthma risk and variants in ORMDL3 and identify a novel risk variant in IL1RL1. Follow-up of the 17q21 deletion in larger cohorts is warranted.

There is evidence that tamoxifen treatment of BRCA1 and BRCA2 carriers for prior breast cancer increases risk of endometrioid subtype endometrial cancer (EC), and suggestive evidence that BRCA1 and BRCA2 mutation carriers may be predisposed to EC in the absence of tamoxifen exposure. We assessed the association of EC with BRCA1 or BRCA2 mutation status in Australasian breast-ovarian families. Report of at least one case of EC was significantly greater in BRCA1-positive families (35/218 (16%); p = .03) and non-significantly greater in BRCA2-positive families (23/189 (12%); p = .6), compared to high-risk breast cancer families without a BRCA1/2 mutation (86/796 (11%)). EC was the first/concurrent cancer for 41% of EC cases with multiple cancer diagnoses from BRCA1/2 families, and early onset for most of these diagnoses. Mutation status was imputed for ungeno-typed individuals from 57 BRCA1/2 pedigrees reporting EC using BRCAPRO. Effects of genotype on EC diagnosis age, and interaction with tamoxifen therapy, were assessed using Cox proportional hazards regression analysis. EC risk was non-significantly marginally greater for BRCA1 carriers (hazard ratio = 1.25, 95%CI = 0.65-2.41), and BRCA2 carriers (HR = 1.12, 95%CI = 0.51-2.45), compared to non-carrier family members. Tamoxifen therapy was highly significantly associated with EC (HR = 6.68, 95%CI = 3.12-15.15; p = 1.7 x 10(-6)) in BRCA1/2 families, with no evidence for interaction between tamoxifen therapy and BRCA1/2 genotype. Our family-based study supports a 7-fold increase in EC risk with tamoxifen exposure for female family members from BRCA1/2 families. Early onset EC in carriers without tamoxifen use suggests that further study is required to assess association of modest EC risk with BRCA1/2 mutation status alone.

Polycystic Kidney Disease is an autosomal dominant disease common in some lines of Bull Terriers (BTPKD). The disease is linked to the canine orthologue of human PKD1 gene, Pkd1, located on CFA06, but no disease-associated mutation has been reported. This study sequenced genomic DNA from two Bull Terriers with BTPKD and two without the disease. A non-synonymous G>A transition mutation in exon 29 of Pkd1 was identified. A TaqMan® SNP Genotyping Assay was designed and demonstrated the heterozygous detection of the mutation in 47 Bull Terriers with BTPKD, but not in 102 Bull Terriers over one year of age and without BTPKD. This missense mutation replaces a glutamic acid residue with a lysine residue in the predicted protein, Polycystin 1. This region of Polycystin 1 is highly conserved between species, and is located in the first cytoplasmic loop of the predicted protein structure, close to the PLAT domain and the second transmembrane region. Thus, this change could alter Polycystin 1 binding or localization. Analytic programs PolyPhen 2, Align GVGD and SIFT predict this mutation to be pathogenic. Thus, BTPKD is associated with a missense mutation in Pkd1, and the application of this mutation specific assay could reduce disease transmission by allowing diagnosis of disease in young animals prior to breeding.