Dog leucocyte antigen (DLA) class II haplotypes and risk of canine diabetes mellitus in specific dog breeds.

BACKGROUND: Canine diabetes mellitus (DM) is a common endocrine disease in domestic dogs. A number of pathological mechanisms are thought to contribute to the aetiopathogenesis of relative or absolute insulin deficiency, including immune-mediated destruction of pancreatic beta cells. DM risk varies considerably between different dog breeds, suggesting that genetic factors are involved and contribute susceptibility or protection. Associations of particular dog leucocyte antigen (DLA) class II haplotypes with DM have been identified, but investigations to date have only considered all breeds pooled together. The aim of this study was to analyse an expanded data set so as to identify breed-specific diabetes-associated DLA haplotypes. METHODS: The 12 most highly represented breeds in the UK Canine Diabetes Register were selected for study. DLA-typing data from 646 diabetic dogs and 912 breed-matched non-diabetic controls were analysed to enable breed-specific analysis of the DLA. Dogs were genotyped for allelic variation at DLA-DRB1, -DQA1, -DQB1 loci using DNA sequence-based typing. Genotypes from all three loci were combined to reveal three-locus DLA class II haplotypes, which were evaluated for statistical associations with DM. This was performed for each breed individually and for all breeds pooled together. RESULTS: Five dog breeds were identified as having one or more DLA haplotype associated with DM susceptibility or protection. Four DM-associated haplotypes were identified in the Cocker Spaniel breed, of which one haplotype was shared with Border Terriers. In the three breeds known to be at highest risk of DM included in the study (Samoyed, Tibetan Terrier and Cairn Terrier), no DLA haplotypes were found to be associated with DM. CONCLUSIONS: Novel DLA associations with DM in specific dog breeds provide further evidence that immune response genes contribute susceptibility to this disease in some cases. It is also apparent that DLA may not be contributing obvious or strong risk for DM in some breeds, including the seven breeds analysed for which no associations were identified.

Route to improving Type 1 diabetes mellitus glycaemic outcomes: real-world evidence taken from the National Diabetes Audit.

AIM: To use general practice-level data for England, available through the National Diabetes Audit, and primary care prescribing data to identify prescription treatment factors associated with variations in achieved glucose control (HbA1c ). METHODS: General practice-level National Diabetes Audit data on Type 1 diabetes, including details of population characteristics, services, proportion of people achieving target glycaemic control [HbA1c ≤58 mmol/mol (7.5%)] and proportion of people at high glycaemic risk [HbA1c >86 mmol/ml (10%)], were linked to 2013-2016 primary care diabetes prescribing data on insulin types and blood glucose monitoring for all people with diabetes. RESULTS: A wide variation was found between the 10th percentile and the 90th percentile of general practices in both target glycaemic control (15.6% to 44.8%, respectively) and high glycaemic risk (4.8% to 28.6%, respectively). Our analysis suggests that, given the extrapolated total of 280 000 people with Type 1 diabetes in the UK, there may be the potential to increase the number of those within target glycaemic control from 80 000 to 101 000; 53% of this increase (11 000 people) would result from service improvements and 47% (10 000 people) from medication and technology changes. The same improvements would also provide the opportunity to reduce the number of people at high glycaemic risk from 42 000 to 26 500. A key factor associated with practice-level target HbA1c achievement would be greater use of insulin pumps for up to an additional 56 000 people. CONCLUSION: If the HbA1c achievement rates in service provision, medication and use of technology currently seen in practices in the 90th percentile were to be matched with regard to HbA1c achievement rates in all general practices, glycaemic control might be improved for 36 500 people, with all the attendant health benefits.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

This corrects the article DOI: 10.1038/mp.2016.244.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

Examining non-syndromic autosomal recessive intellectual disability (NS-ARID) genes for an enriched association with intelligence differences.

Two themes are emerging regarding the molecular genetic aetiology of intelligence. The first is that intelligence is influenced by many variants and those that are tagged by common single nucleotide polymorphisms account for around 30% of the phenotypic variation. The second, in line with other polygenic traits such as height and schizophrenia, is that these variants are not randomly distributed across the genome but cluster in genes that work together. Less clear is whether the very low range of cognitive ability (intellectual disability) is simply one end of the normal distribution describing individual differences in cognitive ability across a population. Here, we examined 40 genes with a known association with non-syndromic autosomal recessive intellectual disability (NS-ARID) to determine if they are enriched for common variants associated with the normal range of intelligence differences. The current study used the 3511 individuals of the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium. In addition, a text mining analysis was used to identify gene sets biologically related to the NS-ARID set. Gene-based tests indicated that genes implicated in NS-ARID were not significantly enriched for quantitative trait loci (QTL) associated with intelligence. These findings suggest that genes in which mutations can have a large and deleterious effect on intelligence are not associated with variation across the range of intelligence differences.

A TOMM40 poly-T variant modulates gene expression and is associated with vocabulary ability and decline in nonpathologic aging.

The Translocase of Outer Mitochondrial Membrane 40 Homolog and Apolipoprotein E (TOMM40-APOE) locus has been associated with a number of age-related phenotypes in humans including nonpathologic cognitive aging, late-onset Alzheimer's disease, and longevity. Here, we investigate the influence of the TOMM40 intron 6 poly-T variant (rs10524523) on TOMM40 gene expression and cognitive abilities and decline in a cohort of 1613 community-dwelling elderly volunteers who had been followed for changes in cognitive functioning over a period of 14 years (range = 12-18 years). We showed that the shorter length poly-T variants were found to act as a repressor of luciferase gene expression in reporter gene constructs. Expression was reduced to approximately half of that observed for the very long variant. We further observed that the shorter poly-T variant was significantly associated with reduced vocabulary ability and a slower rate of vocabulary decline with age compared to the very long poly-T variants. No significant associations were observed for memory, fluid intelligence or processing speed, although the direction of effect, where the short variant was correlated with reduced ability and slower rate of decline was observed for all tests. Our results indicate that the poly-T variant has the ability to interact with transcription machinery and differentially modulate reporter gene expression and influence vocabulary ability and decline with age.

Genome-wide autozygosity is associated with lower general cognitive ability.

Inbreeding depression refers to lower fitness among offspring of genetic relatives. This reduced fitness is caused by the inheritance of two identical chromosomal segments (autozygosity) across the genome, which may expose the effects of (partially) recessive deleterious mutations. Even among outbred populations, autozygosity can occur to varying degrees due to cryptic relatedness between parents. Using dense genome-wide single-nucleotide polymorphism (SNP) data, we examined the degree to which autozygosity associated with measured cognitive ability in an unselected sample of 4854 participants of European ancestry. We used runs of homozygosity-multiple homozygous SNPs in a row-to estimate autozygous tracts across the genome. We found that increased levels of autozygosity predicted lower general cognitive ability, and estimate a drop of 0.6 s.d. among the offspring of first cousins (P=0.003-0.02 depending on the model). This effect came predominantly from long and rare autozygous tracts, which theory predicts as more likely to be deleterious than short and common tracts. Association mapping of autozygous tracts did not reveal any specific regions that were predictive beyond chance after correcting for multiple testing genome wide. The observed effect size is consistent with studies of cognitive decline among offspring of known consanguineous relationships. These findings suggest a role for multiple recessive or partially recessive alleles in general cognitive ability, and that alleles decreasing general cognitive ability have been selected against over evolutionary time.

Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes.

Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (P<5×10(-8)) in GWAS were identified in the major histocompatibility complex (MHC) region for all myositis phenotypes together, as well as for the four clinical and autoantibody phenotypes studied separately. Imputation and regression analyses found that alleles comprising the human leukocyte antigen (HLA) 8.1 ancestral haplotype (AH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations.

CTLA-4 as a genetic determinant in autoimmune Addison's disease.

In common with several other autoimmune diseases, autoimmune Addison's disease (AAD) is thought to be caused by a combination of deleterious susceptibility polymorphisms in several genes, together with undefined environmental factors and stochastic events. To date, the strongest genomic association with AAD has been with alleles at the HLA locus, DR3-DQ2 and DR4. The contribution of other genetic variants has been inconsistent. We have studied the association of 16 single-nucleotide polymorphisms (SNPs) within the CD28-CTLA-4-ICOS genomic locus, in a cohort comprising 691 AAD patients of Norwegian and UK origin with matched controls. We have also performed a meta-analysis including 1002 patients from European countries. The G-allele of SNP rs231775 in CTLA-4 is associated with AAD in Norwegian patients (odds ratio (OR)=1.35 (confidence interval (CI) 1.10-1.66), P=0.004), but not in UK patients. The same allele is associated with AAD in the total European population (OR=1.37 (CI 1.13-1.66), P=0.002). A three-marker haplotype, comprising PROMOTER_1661, rs231726 and rs1896286 was found to be associated with AAD in the Norwegian cohort only (OR 2.43 (CI 1.68-3.51), P=0.00013). This study points to the CTLA-4 gene as a susceptibility locus for the development of AAD, and refines its mapping within the wider genomic locus.

A novel association between COMT and BDNF gene polymorphisms and likelihood of symptomatic dysphagia in older people.

BACKGROUND: Catechol-O-methyl transferase (COMT) and brain-derived neurotrophic factor (BDNF) are neuro-modulatory proteins that have been demonstrated to affect cortical plasticity, which in turn has been shown to affect age-related changes and neuronal functioning in humans. Here, we tested the hypothesis that single nucleotide polymorphisms (SNP) within COMT and BDNF genes are associated with dysphagia in older adults. METHODS: A total of 800 community-dwelling older individuals were sent the Sydney Oropharyngeal Dysphagia Questionnaire to identify swallowing difficulties. DNA from this population was available for study and used to genotype 18 COMT and 12 BDNF polymorphisms. Logistic regression statistical models were used to identify potential associations between dysphagia and the genotypes. KEY RESULTS: A total of 638 individuals completed the questionnaire, giving an 80% response rate. Of these, 538 were genotyped for COMT and BDNF polymorphisms. Age was found to predict dysphagia (p = 0.018, OR = 1.08, CI = 1.01-1.14). The COMT polymorphism rs165599 and the BDNF polymorphism rs10835211 were found to predict dysphagia and have an interactive effect (p = 0.028), which varied according to the carrier status of the other. In the case of SNP rs10835211, the effect of heterozygosity was protective or harmful dependent on the respective status of rs165599. CONCLUSIONS & INFERENCES: These results suggest that certain interactions between plasticity genes contribute to the development of dysphagia with increasing age. This highlights a possible role for genetic factors in future monitoring and treating individuals affected by dysphagia.

Homozygosity in the ApoE 4 polymorphism is associated with dysphagic symptoms in older adults.

Apolipoprotein E (ApoE) is the most well-described genetic risk factor for Alzheimer's disease and nonpathological cognitive decline. While possession of the E2 allele may have protective properties, substantial research evidence suggests the E4 allele increases the risk of cognitive degeneration. As neurodegenerative processes are implicated in swallowing dysfunction, we hypothesized that the presence of ApoE 4 would be predictive of dysphagia symptoms in older adults. Eight hundred members of a genetically well characterized community dwelling elderly cohort received the Sydney oropharyngeal dysphagia questionnaire via mail. Cognitive function was also measured using the modified Telephone Interview of Cognitive Status (TiCS-m) and depression with the Geriatric Depression Score (GDS). ApoE allele was genotyped on blood samples from all subjects and data analyzed using standard statistical software (SPSS version 16). Completed questionnaire response rate was 79% (23.5% men, 76.5% women; mean age 81 ± 5 years; range 69-98 years). Possession of one or more of the ApoE 4 and 2 alleles was found in 23.5% and 16%, respectively. Swallowing score was significantly related to GDS (rho 0.133, P < 0.001**) and age (rho 0.107, P < 0.007**) but not general cognitive function as measured by TICS-m. Self-reported swallowing function was not significantly associated with heterozygosity of any allele or homozygosity for E2 or E3 alleles. Although infrequent (1.1% of all subjects) ApoE E4 homozygosity was significantly associated with higher swallowing scores compared to all other allele combinations (P = 0.033) and while attenuated, was still predicted in multivariate regression modeling (B = 0.812; SE = 0.323; P = 0.012). We report the association between ApoE 4 homozygous genotype and self-reported oropharyngeal dysphagia symptoms in community-dwelling older adults. As this association is weakened by the multivariate analysis and the population frequency of ApoE 4 allele homozygosity is low, this finding while intriguing requires replication in larger independent cohorts.

GWAS-based pathway analysis differentiates between fluid and crystallized intelligence.

Cognitive abilities vary among people. About 40-50% of this variability is due to general intelligence (g), which reflects the positive correlation among individuals' scores on diverse cognitive ability tests. g is positively correlated with many life outcomes, such as education, occupational status and health, motivating the investigation of its underlying biology. In psychometric research, a distinction is made between general fluid intelligence (gF) - the ability to reason in novel situations - and general crystallized intelligence (gC) - the ability to apply acquired knowledge. This distinction is supported by developmental and cognitive neuroscience studies. Classical epidemiological studies and recent genome-wide association studies (GWASs) have established that these cognitive traits have a large genetic component. However, no robust genetic associations have been published thus far due largely to the known polygenic nature of these traits and insufficient sample sizes. Here, using two GWAS datasets, in which the polygenicity of gF and gC traits was previously confirmed, a gene- and pathway-based approach was undertaken with the aim of characterizing and differentiating their genetic architecture. Pathway analysis, using genes selected on the basis of relaxed criteria, revealed notable differences between these two traits. gF appeared to be characterized by genes affecting the quantity and quality of neurons and therefore neuronal efficiency, whereas long-term depression (LTD) seemed to underlie gC. Thus, this study supports the gF-gC distinction at the genetic level and identifies functional annotations and pathways worthy of further investigation.

Genome-wide association study identifies genomic regions of association for cruciate ligament rupture in Newfoundland dogs.

Cranial cruciate ligament rupture (CCLR) is the most common cause of pelvic limb lameness in dogs. To investigate the genetic basis of canine CCLR, we conducted a genome-wide association study using a canine SNP array in Newfoundland pedigree dogs with and without CCLR (n = 96). We identified three main chromosomal regions of CCLR association (on chromosomes 1, 3 and 33). Each of these regions was confirmed by Sequenom genotyping in a further cohort of Newfoundlands (n = 271). The results, particularly SNPs identified in the SORCS2 and SEMA5B genes, suggest that there may be neurological pathways involved in susceptibility to canine CCLR.

Human cognitive ability is influenced by genetic variation in components of postsynaptic signalling complexes assembled by NMDA receptors and MAGUK proteins.

Differences in general cognitive ability (intelligence) account for approximately half of the variation in any large battery of cognitive tests and are predictive of important life events including health. Genome-wide analyses of common single-nucleotide polymorphisms indicate that they jointly tag between a quarter and a half of the variance in intelligence. However, no single polymorphism has been reliably associated with variation in intelligence. It remains possible that these many small effects might be aggregated in networks of functionally linked genes. Here, we tested a network of 1461 genes in the postsynaptic density and associated complexes for an enriched association with intelligence. These were ascertained in 3511 individuals (the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium) phenotyped for general cognitive ability, fluid cognitive ability, crystallised cognitive ability, memory and speed of processing. By analysing the results of a genome wide association study (GWAS) using Gene Set Enrichment Analysis, a significant enrichment was found for fluid cognitive ability for the proteins found in the complexes of N-methyl-D-aspartate receptor complex; P=0.002. Replication was sought in two additional cohorts (N=670 and 2062). A meta-analytic P-value of 0.003 was found when these were combined with the CAGES consortium. The results suggest that genetic variation in the macromolecular machines formed by membrane-associated guanylate kinase (MAGUK) scaffold proteins and their interaction partners contributes to variation in intelligence.

Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT).

It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia (SCZ), evident before full illness onset and independent of medication. The possibility of genetic overlap between risk for SCZ and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with SCZ; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of SCZ have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common single-nucleotide polymorphisms (SNPs) of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for SCZ. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large-scale cognitive GWAS meta-analysis (~5000 individuals from nine nonclinical cohorts comprising the Cognitive Genomics consorTium (COGENT)) to four SCZ case-control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for SCZ were associated with lower general cognitive ability. In addition, using our large cognitive meta-analytic data set, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with SCZ susceptibility. Results provide molecular confirmation of the genetic overlap between SCZ and general cognitive ability, and may provide additional insight into pathophysiology of the disorder.

A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing.

Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality of life and loss of independence in old age. We investigated the genetic contribution to individual differences in nonpathological cognitive ageing in five cohorts of older adults. We undertook a genome-wide association analysis using 549 692 single-nucleotide polymorphisms (SNPs) in 3511 unrelated adults in the Cognitive Ageing Genetics in England and Scotland (CAGES) project. These individuals have detailed longitudinal cognitive data from which phenotypes measuring each individual's cognitive changes were constructed. One SNP--rs2075650, located in TOMM40 (translocase of the outer mitochondrial membrane 40 homolog)--had a genome-wide significant association with cognitive ageing (P=2.5 × 10(-8)). This result was replicated in a meta-analysis of three independent Swedish cohorts (P=2.41 × 10(-6)). An Apolipoprotein E (APOE) haplotype (adjacent to TOMM40), previously associated with cognitive ageing, had a significant effect on cognitive ageing in the CAGES sample (P=2.18 × 10(-8); females, P=1.66 × 10(-11); males, P=0.01). Fine SNP mapping of the TOMM40/APOE region identified both APOE (rs429358; P=3.66 × 10(-11)) and TOMM40 (rs11556505; P=2.45 × 10(-8)) as loci that were associated with cognitive ageing. Imputation and conditional analyses in the discovery and replication cohorts strongly suggest that this effect is due to APOE (rs429358). Functional genomic analysis indicated that SNPs in the TOMM40/APOE region have a functional, regulatory non-protein-coding effect. The APOE region is significantly associated with nonpathological cognitive ageing. The identity and mechanism of one or multiple causal variants remain unclear.

Predicting cognitive ability in ageing cohorts using Type 2 diabetes genetic risk.

AIMS: To investigate whether there is overlap in the genetic determinants of Type 2 diabetes and cognitive ageing by testing whether a genetic risk score for Type 2 diabetes can predict variation in cognitive function in older people without dementia. METHODS: Type 2 diabetes genetic risk scores were estimated using various single nucleotide polymorphism significance inclusion criteria from an initial genome-wide association study, the largest in Type 2 diabetes to date. Scores were available for 2775-3057 individuals, depending on the cognitive trait. RESULTS: Type 2 diabetes genetic risk was associated with self-reported diabetes mellitus. Across varying single nucleotide polymorphism-inclusion levels, a significant association between Type 2 diabetes genetic risk and change in general cognitive function was found (median r = 0.04); however, this was such that higher Type 2 diabetes genetic risk related to higher cognitive scores. CONCLUSIONS: To investigate more fully the source of the often observed comorbidity between Type 2 diabetes and cognitive impairment, one direction for future research will be to use cognitive ability polygenic risk scores to predict Type 2 diabetes in line with the reverse causation hypothesis that people with lower pre-morbid cognitive ability are more likely to develop Type 2 diabetes.

IGF2 gene polymorphisms and IGF-II concentration are determinants of longitudinal weight trends in type 2 diabetes.

The hypothesis of the study was that IGF2 gene polymorphisms were associated with longitudinal trends in weight through modification of IGF-II concentration.Observational study that explored associations of the IGF2 gene and baseline circulating IGF-II concentration with 'real-world' longitudinal trends in body-mass index in a type 2 diabetes population.26 haplotype tagging single nucleotide polymorphisms (SNPs) from the IGF2 and H19 genes were studied in 485 Caucasian individuals in the Salford Longitudinal Diabetes Cohort. A generalised-estimating equation (GEE) model was used to separately study the association of SNPs and IGF-II concentration with 8-year longitudinal trends in body-mass index.High serum IGF-II concentration at baseline was associated with weight loss over the study period (ß=-0.006, 95% CI -0.009 to -0.002, p<0.001). 8 SNPs were associated with longitudinal body-mass index trends, of which 4 retained significance after multiple -testing correction. 2 SNPs rs10770063 and rs3842767 were associated with both IGF-II concentration as well as longitudinal weight changes.We report novel associations between polymorphisms in the IGF2 gene, with concentration of circulating IGF-II and also with longitudinal weight change in type 2 diabetes. Our data indicate that the IGF2 gene and its gene product may be important determinants of longitudinal weight trends in type 2 diabetes.