Genetic influences have an important role in the ageing process. The genetic factors that influence success in bodily ageing may also contribute to the successful ageing of cognitive abilities. A ...comparative genomics approach found longevity genes conserved between yeast Saccharomyces cerevisiae and nematode Caenorhabditis elegans. We hypothesised that these longevity genes influence variance in cognitive ability and age-related cognitive decline in humans. Here, we investigated six of these genes that have human orthologs and show expression in the brain. We tested AFG3L2 (MIM: 604581, AFG3 ATPase family gene 3-like 2 (yeast)), FRAP1 (MIM: 601231, a FK506 binding protein 12-rapamycin associated protein), MAT1A, MAT2A (MIM: 610550 and 601468, methionine adenosyltransferases I alpha and II alpha, respectively), SYNJ1 and SYNJ2 (MIM: 604297 and 609410, synaptojanin-1 and synaptojanin-2, respectively) in approximately 1000 healthy older Scots: the Lothian Birth Cohort 1936 (LBC1936). They were tested on general cognitive ability at age 11 years. At a mean age of 70 years, they re-sat the same general cognitive ability test and underwent an additional battery of diverse cognitive tests. In all, 70 tag and functional SNPs in the six longevity genes were genotyped and tested for association with cognition and cognitive ageing in LBC1936. Suggestive associations were detected between SNPs in SYNJ2, MAT1A, AFG3L2 and SYNJ1 and a general memory factor and general cognitive ability at age 11 and 70 years. Replication studies for cognitive ability associations were performed in 2506 samples from the Cognitive Ageing Genetics in England and Scotland consortium. A meta-analysis replicated the SYNJ2 association with cognitive abilities (lowest P=0.00077). SYNJ2 is a novel gene in which variation is potentially associated with cognitive abilities.
The non-synonymous mutations arg16gly (rs1042713) and gln27glu (rs1042714) in the adrenergic β-2 receptor gene (
ADRB2
) have been associated with cognitive function and brain white matter integrity. ...The current study aimed to replicate these findings and expand them to a broader range of cognitive and brain phenotypes. The sample used is a community-dwelling group of older people, the Lothian Birth Cohort 1936. They had been assessed cognitively at age 11 years, and undertook further cognitive assessments and brain diffusion MRI tractography in older age. The sample size range for cognitive function variables was
N
= 686–765, and for neuroimaging variables was
N
= 488–587. Previously-reported findings with these genetic variants did not replicate in this cohort. Novel, nominally significant associations were observed; notably, the integrity of the left arcuate fasciculus mediated the association between rs1042714 and the Digit Symbol Coding test of information processing speed. No significant associations of cognitive and brain phenotypes with
ADRB2
variants survived correction for false discovery rate. Previous findings may therefore have been subject to type 1 error. Further study into links between
ADRB2
, cognitive function and brain white matter integrity is required.
Neurodevelopmental disorders (NDDs) are complex, polygenic conditions which require genome-wide approaches to dissect their genetic architecture. Additionally, family-based approaches can help in ...understanding the differences in inheritance patterns of NDD-associated loci. Here we use whole-genome sequence data and genome-wide imputed genotype data from 922 individuals from the EU-AIMS Longitudinal European Autism Project (LEAP) cohort to investigate the contributions of both rare and common genetic variants to autism and intellectual disability (ID) outcomes.
Polygenic scores for three NDDs (autism, ADHD, schizophrenia) and two cognitive traits (cognition, educational attainment) were generated using PRSice2. Putatively deleterious SNVs and Indels were filtered using three gene-sets – SFARI (autism-associated loci), DDD (ID associated loci), and brain-expressed, intolerant to loss-of-function loci. CNVs in high-confidence NDD (HC-NDD) loci were also included for analyses. Logistic regression analyses were conducted to assess the relationship between rare and common genetic variation and NDD outcomes. Furthermore, polygenic transmission disequilibrium tests (pTDT) were conducted to assess whether carriers of HC-NDD loci with autism (n= 33) inherit less NDD polygenic risk compared to non-carriers with autism (n= 179).
Polygenic scores for ADHD (P= 2.95e-04; OR= 1.49) and schizophrenia (P = 0.01; OR= 0.76) are associated with NDD outcomes with small local effect size estimates. Interestingly, these results indicate that schizophrenia polygenic score has a potential protective effect against NDD outcomes. HC-NDD CNVs and rare SNVs/Indels were not associated with NDD outcomes. There were no differences observed in polygenic inheritance patterns between carriers of HC-NDD CNVs with autism and non-carriers with autism.
Polygenic scores for ADHD and schizophrenia contribute to NDD outcomes in the LEAP cohort, highlighting their potential in stratifying individuals for NDD diagnostics. Follow-up analyses will be conducted in a cohort of NRXN1 deletion carriers and other NDD databases for comparison.
Intelligence is an important indicator of physical, mental and social well-being. In old age, intelligence is also associated with a higher quality of life and better health. Heritability studies ...have shown that there are strong genetic influences, yet unknown, on intelligence, including in old age. Other approaches may be useful to investigate the biological foundations of intelligence differences. Proteomics is a proven technique in revealing biomarkers for certain illnesses. In this pilot study, forty individuals were selected as the cognitive extremes from over 750 people in the Lothian Birth Cohort 1936 (age ~
72
years) based on their high and low intelligence scores, as measured by a general cognitive ability factor. Urine samples were used as a stable, reliable and abundant source of proteins. Using capillary electrophoresis coupled to mass spectrometry (CE-MS) technology, the proteome of the high and low intelligence groups was determined. Data were calibrated and matched against the human urinary database, to enable comparative assessment. At a nominal significance level (
P
<
0.05), there were several candidate proteins for association with intelligence, including a zinc finger protein (ZNF653) that has been associated with cognitive deficits, and complement C3 and collagen fragments that have been associated with Alzheimer's disease. Results are preliminary, do not survive multiple testing correction, and require validation. This pilot study shows the potential of this novel proteomics approach, and its applicability to understanding the biological foundations of intelligence differences.
Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is ...only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.
Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 ...s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5 × 10(-8)) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered.
Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known.
Perform meta-analyses of ...GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases.
Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV(1) and its ratio to FVC (FEV(1)/FVC) both less than their respective lower limits of normal as determined by published reference equations.
The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV(1)/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis.
These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.
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