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1.  Associations between APOE and low-density lipoprotein cholesterol genotypes and cognitive and physical capability: the HALCyon programme 
Age  2014;36(4):9673.
The APOE ε2/3/4 genotype has been associated with low-density lipoprotein cholesterol (LDL-C) and Alzheimer disease. However, evidence for associations with measures of cognitive performance in adults without dementia has been mixed, as it is for physical performance. Associations may also be evident in other genotypes implicated in LDL-C levels. As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, genotypic information was obtained for APOE ε2/3/4, rs515135 (APOB), rs2228671 (LDLR) and rs629301 (SORT1) from eight cohorts of adults aged between 44 and 90 + years. We investigated associations with four measures of cognitive (word recall, phonemic fluency, semantic fluency and search speed) and physical capability (grip strength, get up and go/walk speed, timed chair rises and ability to balance) using meta-analyses. Overall, little evidence for associations between any of the genotypes and measures of cognitive capability was observed (e.g. pooled beta for APOE ε4 effect on semantic fluency z score = −0.02; 95 % CI = −0.05 to 0.02; p value = 0.3; n = 18,796). However, there was borderline evidence within studies that negative effects of APOE ε4 on nonverbal ability measures become more apparent with age. Few genotypic associations were observed with physical capability measures. The findings from our large investigation of middle-aged to older adults in the general population suggest that effects of APOE on cognitive capability are at most modest and are domain- and age-specific, while APOE has little influence on physical capability. In addition, other LDL-C-related genotypes have little impact on these traits.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-014-9673-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-014-9673-9
PMCID: PMC4150901  PMID: 25073452
Ageing; Apolipoprotein E; Cognition; Single nucleotide polymorphism
2.  A gene-centric analysis of activated partial thromboplastin time and activated protein C resistance using the HumanCVD focused genotyping array 
Activated partial thromboplastin time (aPTT) is an important routine measure of intrinsic blood coagulation. Addition of activated protein C (APC) to the aPTT test to produce a ratio, provides one measure of APC resistance. The associations of some genetic mutations (eg, factor V Leiden) with these measures are established, but associations of other genetic variations remain to be established. The objective of this work was to test for association between genetic variants and blood coagulation using a high-density genotyping array. Genetic association with aPTT and APC resistance was analysed using a focused genotyping array that tests approximately 50 000 single-nucleotide polymorphisms (SNPs) in nearly 2000 cardiovascular candidate genes, including coagulation pathway genes. Analyses were conducted on 2544 European origin women from the British Women's Heart and Health Study. We confirm associations with aPTT at the coagulation factor XII (F12)/G protein-coupled receptor kinase 6 (GRK6) and kininogen 1 (KNG1)/histidine-rich glycoprotein (HRG) loci, and identify novel SNPs at the ABO locus and novel locus kallikrein B (KLKB1)/F11. In addition, we confirm association between APC resistance and factor V Leiden mutation, and identify novel SNP associations with APC resistance in the HRG and F5/solute carrier family 19 member 2 (SLC19A2) regions. In conclusion, variation at several genetic loci influences intrinsic blood coagulation as measured by both aPTT and APC resistance.
doi:10.1038/ejhg.2012.242
PMCID: PMC3682876  PMID: 23188048
aPTT; coagulation; genotype; SNP
3.  Ranking non-synonymous single nucleotide polymorphisms based on disease concepts 
Human Genomics  2014;8(1):11.
As the number of non-synonymous single nucleotide polymorphisms (nsSNPs) identified through whole-exome/whole-genome sequencing programs increases, researchers and clinicians are becoming increasingly reliant upon computational prediction algorithms designed to prioritize potential functional variants for further study. A large proportion of existing prediction algorithms are ‘disease agnostic’ but are nevertheless quite capable of predicting when a mutation is likely to be deleterious. However, most clinical and research applications of these algorithms relate to specific diseases and would therefore benefit from an approach that discriminates between functional variants specifically related to that disease from those which are not. In a whole-exome/whole-genome sequencing context, such an approach could substantially reduce the number of false positive candidate mutations. Here, we test this postulate by incorporating a disease-specific weighting scheme into the Functional Analysis through Hidden Markov Models (FATHMM) algorithm. When compared to traditional prediction algorithms, we observed an overall reduction in the number of false positives identified using a disease-specific approach to functional prediction across 17 distinct disease concepts/categories. Our results illustrate the potential benefits of making disease-specific predictions when prioritizing candidate variants in relation to specific diseases. A web-based implementation of our algorithm is available at http://fathmm.biocompute.org.uk.
doi:10.1186/1479-7364-8-11
PMCID: PMC4083756  PMID: 24980617
SNV; nsSNPs; Disease-causing; Disease-specific; FATHMM; HMMs; SIFT; PolyPhen; Bioinformatics
4.  MeltMADGE for mutation scanning of specific genes in population studies 
Nature protocols  2010;5(11):1800-1812.
MeltMADGE reconfigures the mutation scanning process of denaturing gradient gel electrophoresis (DGGE) so that the independent variable is time rather than space and the dependent (denaturing) variable is temperature rather than concentration of chemical denaturant. Use of a thermal ramp enables use of a homogeneous gel and therefore of high density arrays of wells such as those of microplate array diagonal gel electrophoresis (MADGE). In this configuration, electrophoresis of products on 10-12 96-well meltMADGE gels can be conducted in a 1-2 litre tank in a 1-2hour run, enabling the scanning of a target amplicon in over 1,000 subjects simultaneously. Gels are read by imaging fluorescence of UV-excited ethidium bromide, giving a simple, economical system for identifying rarer sequence variants in target genes which is suitable for large-scale case-control or population studies and other comparable applications. Different amplicons with similar melting characteristics can also be combined into the same run.
doi:10.1038/nprot.2010.136
PMCID: PMC3575632  PMID: 21030955
5.  From a single whole exome read to notions of clinical screening: primary ciliary dyskinesia and RSPH9 p.Lys268del in the Arabian Peninsula 
Annals of human genetics  2012;76(3):211-220.
SUMMARY
Primary ciliary dyskinesia (PCD) is a genetic disorder, usually autosomal recessive, causing early respiratory disease and later subfertility. Whole exome sequencing may enable efficient analysis for locus heterogeneous disorders such as PCD. We whole exome sequenced one consanguineous Saudi Arabian with clinically diagnosed PCD and normal laterality, to attempt ab initio molecular diagnosis.
We reviewed thirteen known PCD genes and potentially autozygous regions (extended homozygosity) for homozygous exon deletions, non-dbSNP codon, splice-site base variants or small indels. Homozygous non-dbSNP changes were also reviewed exome-wide.
One single molecular read representing RSPH9 p.Lys268del was observed, with no wildtype reads, and a notable deficiency of mapped reads at this location. Among all observations, RSPH9 was the strongest candidate for causality. Searching unmapped reads revealed seven more mutant reads. Direct assay for p.Lys268del (MboII digest) confirmed homozygosity in the affected individual, then confirmed homozygosity in three siblings with bronchiectasis. Our finding in southwest Saudi Arabia indicates that p.Lys268del, previously observed in two Bedouin families (Israel, UAE) is geographically widespread in the Arabian Peninsula. Analogous with cystic fibrosis CFTR p.Phe508del, screening for RSPH9 p.Lys268del (which lacks sentinel dextrocardia) in those at risk would help in early diagnosis, tailored clinical management, genetic counselling and primary prevention.
doi:10.1111/j.1469-1809.2012.00704.x
PMCID: PMC3575730  PMID: 22384920
high-throughput nucleotide sequencing; primary ciliary dyskinesia; screening
6.  ACTN3 genotype, athletic status and lifecourse physical capability: meta-analysis of the published literature and findings from nine studies 
Human mutation  2011;32(9):1008-1018.
The ACTN3 R577X (rs1815739) genotype has been associated with athletic status and muscle phenotypes, though not consistently. Our objective was to conduct a meta-analysis of the published literature on athletic status and investigate its associations with physical capability in several new population-based studies. Relevant data were extracted from studies in the literature, comparing genotype frequencies between controls and sprint/power and endurance athletes. For lifecourse physical capability, data were used from two studies of adolescents and seven studies in the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, involving individuals aged between 53 and 90+ years. We found evidence from the published literature to support the hypothesis that in Europeans the RR genotype is more common among sprint/power athletes compared with their controls. There is currently no evidence that the X allele is advantageous to endurance athleticism. We found no association between R577X and grip strength (p-value=0.09, n=7672 in males; p-value=0.90, n=7839 in females), standing balance, timed get up and go or chair rises in our studies of physical capability. The ACTN3 R577X genotype is associated with sprint/power athletic status in Europeans, but does not appear to be associated with objective measures of physical capability in the general population.
doi:10.1002/humu.21526
PMCID: PMC3174315  PMID: 21542061
ACTN3; Actinin-3; athlete; aging; SNP; grip strength
7.  ACTN3 Genotype, Athletic Status, and Life Course Physical Capability: Meta-Analysis of the Published Literature and Findings from Nine Studies 
Human Mutation  2011;32(9):1008-1018.
The ACTN3 R577X (rs1815739) genotype has been associated with athletic status and muscle phenotypes, although not consistently. Our objective was to conduct a meta-analysis of the published literature on athletic status and investigate its associations with physical capability in several new population-based studies. Relevant data were extracted from studies in the literature, comparing genotype frequencies between controls and sprint/power and endurance athletes. For life course physical capability, data were used from two studies of adolescents and seven studies in the Healthy Ageing across the Life Course (HALCyon) collaborative research program, involving individuals aged between 53 and 90+ years. We found evidence from the published literature to support the hypothesis that in Europeans the RR genotype is more common among sprint/power athletes compared with their controls. There is currently no evidence that the X allele is advantageous to endurance athleticism. We found no association between R577X and grip strength (P = 0.09, n = 7,672 in males; P = 0.90, n = 7,839 in females), standing balance, timed get up and go, or chair rises in our studies of physical capability. The ACTN3 R577X genotype is associated with sprint/power athletic status in Europeans, but does not appear to be associated with objective measures of physical capability in the general population. Hum Mutat 32:1–11, 2011. © 2011 Wiley-Liss, Inc.
doi:10.1002/humu.21526
PMCID: PMC3174315  PMID: 21542061
ACTN3; Actinin-3; athlete; aging; SNP; grip strength
8.  Absence of association of a SNP in the TERT-CLPTM1L locus with age-related phenotypes in a large multi-cohort study: the HALCyon program 
Aging cell  2011;10(3):520-532.
Summary
Background
Several age-related traits are associated with shorter telomeres, the structures that cap the end of linear chromosomes. A common polymorphism near the telomere maintenance gene TERT has been associated with several cancers, but relationships with other ageing traits such as physical capability have not been reported.
Methods
As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, men and women aged between 44 and 90 years from 9 UK cohorts were genotyped for the single nucleotide polymorphism (SNP) rs401681. We then investigated relationships between the SNP and 30 age-related phenotypes, including cognitive and physical capability, blood lipid levels and lung function, pooling within-study genotypic effects in meta-analyses.
Results
No significant associations were found between the SNP and any of the cognitive performance tests (e.g. pooled beta per T allele for word recall z-score=0.02, 95% CI: -0.01- 0.04, p-value=0.12, n=18,737), physical performance tests (e.g. pooled beta for grip strength=-0.02, 95% CI:-0.045- 0.006, p-value=0.14, n=11,711), blood pressure, lung function or blood test measures. Similarly, no differences in observations were found when considering follow-up measures of cognitive or physical performance after adjusting for its measure at an earlier assessment.
Conclusion
The lack of associations between SNP rs401681 and a wide range of age-related phenotypes investigated in this large multi-cohort study suggests that whilst this SNP may be associated with cancer, it is not an important contributor to other markers of ageing.
doi:10.1111/j.1474-9726.2011.00687.x
PMCID: PMC3094481  PMID: 21332924
Aging; ageing; middle-aged; telomere; cognition; physical
9.  INTERACTION BETWEEN BIRTH-WEIGHT AND POLYMORPHISM IN THE CALCIUM SENSING RECEPTOR GENE IN DETERMINATION OF ADULT BONE MASS: THE HERTFORDSHIRE COHORT STUDY 
The Journal of rheumatology  2007;34(4):769-775.
Objective
We sought evidence of interaction between single nucleotide polymorphisms (SNPs) in the Calcium Sensing Receptor (CASR) gene and early life in determination of bone mineral density (BMD) among individuals from the Hertfordshire Cohort Study.
Methods
Four hundred and ninety eight men and 468 women aged 59-71 years were recruited. A lifestyle questionnaire was administered and BMD at lumbar spine and femoral neck was measured. DNA was obtained from whole blood samples using standard extraction techniques. Five SNPs of the CASR gene termed CASRV1 (rs1801725, G>T, S986A), CASRV2 (rs7614486, T>G, untranslated), CASRV3 (rs4300957, untranslated), CASRV4 (rs3804592 G>A, intron) and CASRV5 (rs1393189, T>C, intron) were analysed.
Results
Among women the 11 genotype of the CASRV3 SNP was associated with higher lumbar spine BMD within the lowest birth-weight tertile, while the opposite pattern was observed among individuals in the highest birth-weight tertile (test for interaction on 1df, p=0.005, adjusted for age, BMI, physical activity, dietary calcium intake, cigarette and alcohol consumption, social class, menopausal status and HRT use). Similar relationships were seen at the total femur (p=0.042, fully adjusted) with birth-weight and at the total femur according to weight at one year tertile among women (p<0.001, fully adjusted). One haplotype was associated with lumbar spine BMD in women (p=0.008, fully adjusted); these findings were replicated in a second cohort.
Conclusion
We have found evidence of an interaction between a SNP of the CASR gene and birth weight in determination of bone mass in a UK female population.
PMCID: PMC2136207  PMID: 17309124
bone; bone density; cohort studies; genetic studies
10.  Cubic exact solutions for the estimation of pairwise haplotype frequencies: implications for linkage disequilibrium analyses and a web tool 'CubeX' 
BMC Bioinformatics  2007;8:428.
Background
The frequency of a haplotype comprising one allele at each of two loci can be expressed as a cubic equation (the 'Hill equation'), the solution of which gives that frequency. Most haplotype and linkage disequilibrium analysis programs use iteration-based algorithms which substitute an estimate of haplotype frequency into the equation, producing a new estimate which is repeatedly fed back into the equation until the values converge to a maximum likelihood estimate (expectation-maximisation).
Results
We present a program, "CubeX", which calculates the biologically possible exact solution(s) and provides estimated haplotype frequencies, D', r2 and χ2 values for each. CubeX provides a "complete" analysis of haplotype frequencies and linkage disequilibrium for a pair of biallelic markers under situations where sampling variation and genotyping errors distort sample Hardy-Weinberg equilibrium, potentially causing more than one biologically possible solution. We also present an analysis of simulations and real data using the algebraically exact solution, which indicates that under perfect sample Hardy-Weinberg equilibrium there is only one biologically possible solution, but that under other conditions there may be more.
Conclusion
Our analyses demonstrate that lower allele frequencies, lower sample numbers, population stratification and a possible |D'| value of 1 are particularly susceptible to distortion of sample Hardy-Weinberg equilibrium, which has significant implications for calculation of linkage disequilibrium in small sample sizes (eg HapMap) and rarer alleles (eg paucimorphisms, q < 0.05) that may have particular disease relevance and require improved approaches for meaningful evaluation.
doi:10.1186/1471-2105-8-428
PMCID: PMC2180187  PMID: 17980034
11.  Refining associations between TAS2R38 diplotypes and the 6-n-propylthiouracil (PROP) taste test: findings from the Avon Longitudinal Study of Parents and Children 
BMC Genetics  2007;8:51.
Background
Previous investigations have highlighted the importance of genetic variation in the determination of bitter tasting ability, however have left unaddressed questions as to within group variation in tasting ability or the possibility of genetic prescription of intermediate tasting ability. Our aim was to examine the relationships between bitter tasting ability and variation at the TAS2R38 locus and to assess the role of psychosocial factors in explaining residual, within group, variation in tasting ability.
Results
In a large sample of children from the Avon Longitudinal Study of Parents and Children, we confirmed an association between bitter compound tasting ability and TAS2R38 variation and found evidence of a genetic association with intermediate tasting ability. Antisocial behaviour, social class and depression showed no consistent relationship with the distribution of taste test scores.
Conclusion
Factors which could influence a child's chosen taste score, extra to taste receptor variation, appeared not to show relationships with test score. Observed spread in the distribution of the taste test scores within hypothesised taster groups, is likely to be, or at least in part, due to physiological differentiation regulated by other genetic contributors. Results confirm relationships between genetic variation and bitter compound tasting ability in a large sample, and suggest that TAS2R38 variation may also be associated with intermediate tasting ability.
doi:10.1186/1471-2156-8-51
PMCID: PMC1964760  PMID: 17662150
12.  MIDAS: software for analysis and visualisation of interallelic disequilibrium between multiallelic markers 
BMC Bioinformatics  2006;7:227.
Background
Various software tools are available for the display of pairwise linkage disequilibrium across multiple single nucleotide polymorphisms. The HapMap project also presents these graphics within their website. However, these approaches are limited in their use of data from multiallelic markers and provide limited information in a graphical form.
Results
We have developed a software package (MIDAS – Multiallelic Interallelic Disequilibrium Analysis Software) for the estimation and graphical display of interallelic linkage disequilibrium. Linkage disequilibrium is analysed for each allelic combination (of one allele from each of two loci), between all pairwise combinations of any type of multiallelic loci in a contig (or any set) of many loci (including single nucleotide polymorphisms, microsatellites, minisatellites and haplotypes). Data are presented graphically in a novel and informative way, and can also be exported in tabular form for other analyses. This approach facilitates visualisation of patterns of linkage disequilibrium across genomic regions, analysis of the relationships between different alleles of multiallelic markers and inferences about patterns of evolution and selection.
Conclusion
MIDAS is a linkage disequilibrium analysis program with a comprehensive graphical user interface providing novel views of patterns of linkage disequilibrium between all types of multiallelic and biallelic markers.
Availability
Available from and
doi:10.1186/1471-2105-7-227
PMCID: PMC1479374  PMID: 16643648
13.  The association of the PON1 Q192R polymorphism with coronary heart disease: findings from the British Women's Heart and Health cohort study and a meta-analysis 
BMC Genetics  2004;5:17.
Background
There have been inconsistent results from case-control studies assessing the association of the PON1 Q192R polymorphism with coronary heart disease (CHD). Most studies have included predominantly men and the association in women is unclear. Since lipid levels vary between the sexes the antioxidant effect of PON1 and any genes associated with it may also vary by sex. We have examined the association of the PON1 Q192R polymorphism with CHD in a large cohort of British women and combined the results from our cohort study with those from all other published studies.
Results
The distribution of genotypes was the same among women with CHD and those without disease. The odds ratio (95% confidence interval) of having CHD comparing those with either the QR or RR genotype to those with QQ genotype (dominant model of association) was 1.03 (0.89, 1.21) and the per allele odds ratio was 0.98 (0.95, 1.01). In a meta-analysis of this and 38 other published studies (10,738 cases and 17,068 controls) the pooled odds ratio for the dominant effect was 1.14 (1.08, 1.20) and for the per allele effect was 1.10 (1.06, 1.13). There was evidence of small study bias in the meta-analyses and the dominant effect among those studies with 500 or more cases was 1.05 (0.96, 1.15). Ethnicity and reporting of whether the genotyping was done blind to the participants clinical status also contributed to heterogeneity between studies, but there was no difference in effect between studies with 50% or more women compared to those with fewer women and no difference between studies of healthy populations compared to those at high risk (with diabetes, renal disease of familial hypercholesterolaemia).
Conclusion
There is no robust evidence that the PON1 Q192R polymorphism is associated with CHD risk in Caucasian women or men.
doi:10.1186/1471-2156-5-17
PMCID: PMC449704  PMID: 15214960
14.  Molecular and Population Analysis of Natural Selection on the Human Haptoglobin Duplication 
Annals of Human Genetics  2012;76(5):352-362.
Haptoglobin binds free haemoglobin that prevents oxidative damage produced by haemolysis. There is a copy number variant (CNV) in the haptoglobin gene (HP) consisting of two alleles, Hp1 (no duplication), and Hp2 (1.7kb duplication involving two exons). The spread of the Hp2 allele is believed to have taken place under selective pressures conferred by malaria resistance. However, molecular evidence is lacking and Hp did not emerge in genomewide SNPs surveys for evidence of selection. In Europe, there is geographical constancy of Hp2 frequency, indicative of absence of clinal pressures and that modern day European alleles represent a “snapshot” of their out-of-Africa migrations. In this work we test for signatures of natural selection acting on the Hp CNV in a sample from the UK population (Avon Longitudinal Study of Parents and Children, ALSPAC). We present here heterozygosity decay, pairwise FST values observed between ALSPAC and 301 populations from all five populated continents, extended haplotype homozygosity analyses involving the CNV and 80 SNPs surrounding the CNV ∼500kb in each direction, and linkage disequilibrium and pairwise haplotypic analyses involving 160 SNPs on chromosome 16q22.1. Taken together, our results represent the first molecular analysis of natural selection in the Hp CNV genetic region.
doi:10.1111/j.1469-1809.2012.00716.x
PMCID: PMC3963445  PMID: 22607059
Haptoglobin; natural selection; copy number variant; ALSPAC

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