Michael E Weale

Publications of Michael E Weale

• Analysis of European case-control studies suggests that common inherited variation in mitochondrial DNA is not involved in susceptibility to amyotrophic lateral sclerosis.

  Authors: Catherine J E Ingram, Michael E Weale, Christopher A Plaster, Karen E Morrison, Emily F Goodall, Hardev S Pall, Marcus Beck, Sibylle Jablonka, Michael Sendtner, Elizabeth M C Fisher, Neil Bradman, Dalia Kasperavičiūtė

  Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases. 03/2012;

  While some cases of familial ALS can be entirely attributed to known inherited variation, the majority (∼90%) are sporadic, where the cause(s) are not entirely understood. Both genetic andWhile some cases of familial ALS can be entirely attributed to known inherited variation, the majority (∼90%) are sporadic, where the cause(s) are not entirely understood. Both genetic and environmental factors may contribute to susceptibility. Mitochondrial damage, a common feature of neurodegenerative disease, is observed in most patients and inherited polymorphism in the mitochondrial genome has been suggested as a contributing factor. We used an economic and efficient method to test whether such involvement is probable.We genotyped 22 mtDNA coding region SNPs and sequenced the mtDNA hypervariable region 1 to determine the position of each mitochondrial genome within the genealogy of mitochondrial haplotypes in samples of ALS patients (n = 700) and controls (n = 462) from two European populations. We compared haplotype and haplogroup distribution in cases and controls drawn from the same populations. No statistical difference was observed between cases and controls at either the haplogroup or haplotype level (p = ≥ 0.2). In conclusion, it is unlikely that common, shared genetic variants in the mitochondrial genome contribute substantially to ALS. Combining the data with other studies will allow meta-analysis to look for variants with modest effect sizes. The sequencing of complete mitochondrial genomes will be required to assess the role of rare mutations.

• Integration of GWAS SNPs and tissue specific expression profiling reveal discrete eQTLs for human traits in blood and brain.

  Authors: Dena G Hernandez, Mike A Nalls, Matthew Moore, Sean Chong, Allissa Dillman, Daniah Trabzuni, J Raphael Gibbs, Mina Ryten, Sampath Arepalli, Michael E Weale, Alan Zonderman, Juan Troncoso, Richard O'Brian, Robert Walker, Colin Smith, Stefania Bandinelli, Bryan J Traynor, John Hardy, Andy B Singleton, Mark R Cookson

  Neurobiology of disease. 03/2012;

  Genome-wide association studies have nominated many genetic variants for common human traits, including diseases, but in many cases the underlying biological reason for a trait association isGenome-wide association studies have nominated many genetic variants for common human traits, including diseases, but in many cases the underlying biological reason for a trait association is unknown. Subsets of genetic polymorphisms show a statistical association with transcript expression levels, and have therefore been nominated as expression quantitative trait loci (eQTL). However, many tissue and cell types have specific gene expression patterns and so it is not clear how frequently eQTLs found in one tissue type will be replicated in others. In the present study we used two appropriately powered sample series to examine the genetic control of gene expression in blood and brain. We find that while many eQTLs associated with human traits are shared between these two tissues, there are also examples where blood and brain differ, either by restricted gene expression patterns in one tissue or because of differences in how genetic variants are associated with transcript levels. These observations suggest that design of eQTL mapping experiments should consider tissue of interest for the disease or other traits studied.

• Quality control parameters on a large dataset of regionally dissected human control brains for whole genome expression studies.

  Authors: Daniah Trabzuni, Mina Ryten, Robert Walker, Colin Smith, Sabaena Imran, Adaikalavan Ramasamy, Michael E Weale, John Hardy

  Journal of neurochemistry. 08/2011; 119(2):275-82.

  We are building an open-access database of regional human brain expression designed to allow the genome-wide assessment of genetic variability on expression. Array and RNA sequencing technologiesWe are building an open-access database of regional human brain expression designed to allow the genome-wide assessment of genetic variability on expression. Array and RNA sequencing technologies make assessment of genome-wide expression possible. Human brain tissue is a challenging source for this work because it can only be obtained several and variable hours post-mortem and after varying agonal states. These variables alter RNA integrity in a complex manner. In this report, we assess the effect of post-mortem delay, agonal state and age on gene expression, and the utility of pH and RNA integrity number as predictors of gene expression as measured on 1266 Affymetrix Exon Arrays. We assessed the accuracy of the array data using QuantiGene, as an independent non-PCR-based method. These quality control parameters will allow database users to assess data accuracy. We report that within the parameters of this study post-mortem delay, agonal state and age have little impact on array quality, array data are robust to variable RNA integrity, and brain pH has only a small effect on array performance. QuantiGene gave very similar expression profiles as array data. This study is the first step in our initiative to make human, regional brain expression freely available.

• Using functional annotation for the empirical determination of Bayes Factors for genome-wide association study analysis.

  Authors: Jo Knight, Michael R Barnes, Gerome Breen, Michael E Weale

  PloS one. 01/2011; 6(4):e14808.

  A genome wide association study (GWAS) typically results in a few highly significant 'hits' and a much larger set of suggestive signals ('near-hits'). The latter group are expected to be a mixture ofA genome wide association study (GWAS) typically results in a few highly significant 'hits' and a much larger set of suggestive signals ('near-hits'). The latter group are expected to be a mixture of true and false associations. One promising strategy to help separate these is to use functional annotations for prioritisation of variants for follow-up. A key task is to determine which annotations might prove most valuable. We address this question by examining the functional annotations of previously published GWAS hits. We explore three annotation categories: non-synonymous SNPs (nsSNPs), promoter SNPs and cis expression quantitative trait loci (eQTLs) in open chromatin regions. We demonstrate that GWAS hit SNPs are enriched for these three functional categories, and that it would be appropriate to provide a higher weighting for such SNPs when performing Bayesian association analyses. For GWAS studies, our analyses suggest the use of a Bayes Factor of about 4 for cis eQTL SNPs within regions of open chromatin, 3 for nsSNPs and 2 for promoter SNPs.

• Genes predict village of origin in rural Europe.

  Authors: Colm O'Dushlaine, Ruth McQuillan, Michael E Weale, Daniel J M Crouch, Asa Johansson, Yurii Aulchenko, Christopher S Franklin, Ozren Polašek, Christian Fuchsberger, Aiden Corvin [......] Caroline Hayward, Sarah H Wild, Thomas Meitinger, Cornelia M van Duijn, Ulf Gyllensten, Alan F Wright, Harry Campbell, Peter P Pramstaller, Igor Rudan, James F Wilson

  European journal of human genetics : EJHG. 11/2010; 18(11):1269-70.

  The genetic structure of human populations is important in population genetics, forensics and medicine. Using genome-wide scans and individuals with all four grandparents born in the same settlement,The genetic structure of human populations is important in population genetics, forensics and medicine. Using genome-wide scans and individuals with all four grandparents born in the same settlement, we here demonstrate remarkable geographical structure across 8-30  km in three different parts of rural Europe. After excluding close kin and inbreeding, village of origin could still be predicted correctly on the basis of genetic data for 89-100% of individuals.

• A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.

  Authors: Amy Strange, Francesca Capon, Chris C A Spencer, Jo Knight, Michael E Weale, Michael H Allen, Anne Barton, Gavin Band, Céline Bellenguez, Judith G M Bergboer [......] Christopher E M Griffiths, Juha Kere, André Reis, Gilean McVean, David M Evans, Matthew A Brown, Jonathan N Barker, Leena Peltonen, Peter Donnelly, Richard C Trembath

  Nature genetics. 11/2010; 42(11):985-90.

  To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations atTo identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These associations were replicated in 9,079 European samples (six loci with a combined P < 5 × 10⁻⁸ and two loci with a combined P < 5 × 10⁻⁷). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 × 10⁻⁶). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele. Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis.

• Increased prevalence of M694V in patients with ankylosing spondylitis: additional evidence for a link with familial mediterranean fever.

  Authors: Nurullah Akkoc, Ismail Sari, Servet Akar, Omer Binicier, Mark G Thomas, Michael E Weale, Merih Birlik, Yusuf Savran, Fatos Onen, Neil Bradman, Christopher A Plaster

  Arthritis and rheumatism. 10/2010; 62(10):3059-63.

  To assess whether there is a statistically significant difference in the frequency of common MEFV allele variants in patients with ankylosing spondylitis (AS) as compared with control patients withTo assess whether there is a statistically significant difference in the frequency of common MEFV allele variants in patients with ankylosing spondylitis (AS) as compared with control patients with rheumatoid arthritis (RA) and with healthy control subjects. Sixty-two patients with AS, 50 healthy control subjects, and 46 patients with RA were assessed for the presence of MEFV variants. Exon 10 was analyzed by direct sequencing. E148Q was analyzed by restriction endonuclease enzyme digestion (REED) or by direct sequencing when REED analysis failed. The allele frequency of all MEFV variants in the AS group was significantly higher than that in the pooled control group of healthy subjects plus RA patients (15.3% versus 6.8%; P = 0.021). M694V was the only variant that was significantly more common in the AS group than in the combined or individual control groups (P = 0.026 for AS patients versus healthy controls, P = 0.046 for AS patients versus RA patient controls, and P = 0.008 for AS patients versus healthy and RA patient control groups). The carriage rate of M694V was also significantly higher in the AS patient group than in the combined control group (odds ratio 7.0, P = 0.014). Neither M694V nor any other MEFV variant showed a correlation with most of the disease-related measures examined. We found an increased frequency of MEFV variants in AS patients as compared with healthy controls and with RA patient controls. This was primarily due to the presence of M694V. The roles of other exon 10 variants, as well as the relationship between the variant status and the severity and clinical course of the disease, need to be explored in further studies that include sufficiently large sample sizes.

• Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study.

  Authors: Aleksey Shatunov, Kin Mok, Stephen Newhouse, Michael E Weale, Bradley Smith, Caroline Vance, Lauren Johnson, Jan H Veldink, Michael A van Es, Leonard H van den Berg [......] Hardev Pall, P Nigel Leigh, John Hardy, Robert H Brown, John F Powell, Richard W Orrell, Karen E Morrison, Pamela J Shaw, Christopher E Shaw, Ammar Al-Chalabi

  Lancet neurology. 10/2010; 9(10):986-94.

  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons that results in progressive weakness and death from respiratory failure, commonly within about 3 years. PreviousAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons that results in progressive weakness and death from respiratory failure, commonly within about 3 years. Previous studies have shown association of a locus on chromosome 9p with ALS and linkage with ALS-frontotemporal dementia. We aimed to test whether this genomic region is also associated with ALS in an independent set of UK samples, and to identify risk factors associated with ALS in a further genome-wide association study that combined data from the independent analysis with those from other countries. We collected samples from patients with sporadic ALS from 20 UK hospitals and obtained UK control samples from the control groups of the Depression Case Control study, the Bipolar Affective Case Control Study, and the British 1958 birth cohort DNA collection. Genotyping of DNA in this independent analysis was done with Illumina HumanHap550 BeadChips. We then undertook a joint genome-wide analysis that combined data from the independent set with published data from the UK, USA, Netherlands, Ireland, Italy, France, Sweden, and Belgium. The threshold for significance was p=0·05 in the independent analysis, because we were interested in replicating a small number of previously reported associations, whereas the Bonferroni-corrected threshold for significance in the joint analysis was p=2·20×10(-7) After quality control, samples were available from 599 patients and 4144 control individuals in the independent set. In this analysis, two single nucleotide polymorphisms in a locus on chromosome 9p21.2 were associated with ALS: rs3849942 (p=2·22×10(-6); odds ratio [OR] 1·39, 95% CI 1·21-1·59) and rs2814707 (p=3·32×10(-6); 1·38, 1·20-1·58). In the joint analysis, which included samples from 4312 patients with ALS and 8425 control individuals, rs3849942 (p=4·64×10(-10); OR 1·22, 95% CI 1·15-1·30) and rs2814707 (p=4·72×10(-10); 1·22, 1·15-1·30) were associated with ALS. We have found strong evidence of a genetic association of two single nucleotide polymorphisms on chromosome 9 with sporadic ALS, in line with findings from previous independent GWAS of ALS and linkage studies of ALS-frontotemporal dementia. Our findings together with these earlier findings suggest that genetic variation at this locus on chromosome 9 causes sporadic ALS and familial ALS-frontotemporal dementia. Resequencing studies and then functional analysis should be done to identify the defective gene.

• Genome-wide association study of major recurrent depression in the U.K. population.

  Authors: Cathryn M Lewis, Mandy Y Ng, Amy W Butler, Sarah Cohen-Woods, Rudolf Uher, Katrina Pirlo, Michael E Weale, Alexandra Schosser, Ursula M Paredes, Margarita Rivera [......] Pierandrea Muglia, Michael R Barnes, John C Whittaker, Federica Tozzi, Florian Holsboer, Martin Preisig, Anne E Farmer, Gerome Breen, Ian W Craig, Peter McGuffin

  The American journal of psychiatry. 08/2010; 167(8):949-57.

  Studies of major depression in twins and families have shown moderate to high heritability, but extensive molecular studies have failed to identify susceptibility genes convincingly. To detectStudies of major depression in twins and families have shown moderate to high heritability, but extensive molecular studies have failed to identify susceptibility genes convincingly. To detect genetic variants contributing to major depression, the authors performed a genome-wide association study using 1,636 cases of depression ascertained in the U.K. and 1,594 comparison subjects screened negative for psychiatric disorders. Cases were collected from 1) a case-control study of recurrent depression (the Depression Case Control [DeCC] study; N=1346), 2) an affected sibling pair linkage study of recurrent depression (probands from the Depression Network [DeNT] study; N=332), and 3) a pharmacogenetic study (the Genome-Based Therapeutic Drugs for Depression [GENDEP] study; N=88). Depression cases and comparison subjects were genotyped at Centre National de Génotypage on the Illumina Human610-Quad BeadChip. After applying stringent quality control criteria for missing genotypes, departure from Hardy-Weinberg equilibrium, and low minor allele frequency, the authors tested for association to depression using logistic regression, correcting for population ancestry. Single nucleotide polymorphisms (SNPs) in BICC1 achieved suggestive evidence for association, which strengthened after imputation of ungenotyped markers, and in analysis of female depression cases. A meta-analysis of U.K. data with previously published results from studies in Munich and Lausanne showed some evidence for association near neuroligin 1 (NLGN1) on chromosome 3, but did not support findings at BICC1. This study identifies several signals for association worthy of further investigation but, as in previous genome-wide studies, suggests that individual gene contributions to depression are likely to have only minor effects, and very large pooled analyses will be required to identify them.

• Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders.

  Authors: Cynthia M Beall, Gianpiero L Cavalleri, Libin Deng, Robert C Elston, Yang Gao, Jo Knight, Chaohua Li, Jiang Chuan Li, Yu Liang, Mark McCormack [......] Michael E Weale, Yaomin Xu, Zhe Xu, Ling Yang, M Justin Zaman, Changqing Zeng, Li Zhang, Xianglong Zhang, Pingcuo Zhaxi, Yong Tang Zheng

  Proceedings of the National Academy of Sciences of the United States of America. 06/2010; 107(25):11459-64.

  By impairing both function and survival, the severe reduction in oxygen availability associated with high-altitude environments is likely to act as an agent of natural selection. We used genomic andBy impairing both function and survival, the severe reduction in oxygen availability associated with high-altitude environments is likely to act as an agent of natural selection. We used genomic and candidate gene approaches to search for evidence of such genetic selection. First, a genome-wide allelic differentiation scan (GWADS) comparing indigenous highlanders of the Tibetan Plateau (3,200-3,500 m) with closely related lowland Han revealed a genome-wide significant divergence across eight SNPs located near EPAS1. This gene encodes the transcription factor HIF2alpha, which stimulates production of red blood cells and thus increases the concentration of hemoglobin in blood. Second, in a separate cohort of Tibetans residing at 4,200 m, we identified 31 EPAS1 SNPs in high linkage disequilibrium that correlated significantly with hemoglobin concentration. The sex-adjusted hemoglobin concentration was, on average, 0.8 g/dL lower in the major allele homozygotes compared with the heterozygotes. These findings were replicated in a third cohort of Tibetans residing at 4,300 m. The alleles associating with lower hemoglobin concentrations were correlated with the signal from the GWADS study and were observed at greatly elevated frequencies in the Tibetan cohorts compared with the Han. High hemoglobin concentrations are a cardinal feature of chronic mountain sickness offering one plausible mechanism for selection. Alternatively, as EPAS1 is pleiotropic in its effects, selection may have operated on some other aspect of the phenotype. Whichever of these explanations is correct, the evidence for genetic selection at the EPAS1 locus from the GWADS study is supported by the replicated studies associating function with the allelic variants.

• Delta-centralization fails to control for population stratification in genetic association studies.

  Authors: Tony Dadd, Cathryn M Lewis, Michael E Weale

  Human heredity. 04/2010; 69(4):285-94.

  To investigate the validity of simulations and assumptions used to underpin the delta-centralization (DC) method for correcting for population stratification in genetic association studies; to assessTo investigate the validity of simulations and assumptions used to underpin the delta-centralization (DC) method for correcting for population stratification in genetic association studies; to assess the effectiveness of DC compared to genomic control (GC) under valid simulation conditions; and to highlight other studies employing similarly flawed simulations. DC and GC use data from unlinked null loci to correct the test statistic at the target locus, but differ in the way the correction is performed. We compare DC and GC under two simulation approaches: an invalid approach adopted by the originators of DC, which permits subpopulation allele frequency matching of null markers to the target locus; and a valid approach, based on the Balding-Nichols model, which does not allow subpopulation matching. DC works under invalid simulation conditions (subpopulation allele frequency matching), but not under our valid ones. We use theoretical arguments to assert that there are no valid conditions under which DC might work. We identify several studies which have adopted similarly invalid simulation approaches in this field. DC fails to control for population stratification and should not be used. Other results from studies which have used the same invalid simulation approach should be treated cautiously.

• Little genetic differentiation as assessed by uniparental markers in the presence of substantial language variation in peoples of the Cross River region of Nigeria.

  Authors: Krishna R Veeramah, Bruce A Connell, Naser Ansari Pour, Adam Powell, Christopher A Plaster, David Zeitlyn, Nancy R Mendell, Michael E Weale, Neil Bradman, Mark G Thomas

  BMC evolutionary biology. 03/2010; 10:92.

  The Cross River region in Nigeria is an extremely diverse area linguistically with over 60 distinct languages still spoken today. It is also a region of great historical importance, being a) adjacentThe Cross River region in Nigeria is an extremely diverse area linguistically with over 60 distinct languages still spoken today. It is also a region of great historical importance, being a) adjacent to the likely homeland from which Bantu-speaking people migrated across most of sub-Saharan Africa 3000-5000 years ago and b) the location of Calabar, one of the largest centres during the Atlantic slave trade. Over 1000 DNA samples from 24 clans representing speakers of the six most prominent languages in the region were collected and typed for Y-chromosome (SNPs and microsatellites) and mtDNA markers (Hypervariable Segment 1) in order to examine whether there has been substantial gene flow between groups speaking different languages in the region. In addition the Cross River region was analysed in the context of a larger geographical scale by comparison to bordering Igbo speaking groups as well as neighbouring Cameroon populations and more distant Ghanaian communities. The Cross River region was shown to be extremely homogenous for both Y-chromosome and mtDNA markers with language spoken having no noticeable effect on the genetic structure of the region, consistent with estimates of inter-language gene flow of 10% per generation based on sociological data. However the groups in the region could clearly be differentiated from others in Cameroon and Ghana (and to a lesser extent Igbo populations). Significant correlations between genetic distance and both geographic and linguistic distance were observed at this larger scale. Previous studies have found significant correlations between genetic variation and language in Africa over large geographic distances, often across language families. However the broad sampling strategies of these datasets have limited their utility for understanding the relationship within language families. This is the first study to show that at very fine geographic/linguistic scales language differences can be maintained in the presence of substantial gene flow over an extended period of time and demonstrates the value of dense sampling strategies and having DNA of known and detailed provenance, a practice that is generally rare when investigating sub-Saharan African demographic processes using genetic data.

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• Quality control for genome-wide association studies.

  Authors: Michael E Weale

  Methods in molecular biology (Clifton, N.J.). 01/2010; 628:341-72.

  This chapter is a comprehensive review of quality control (QC) methods for SNP-based genotyping panels used in genome-wide association studies. These include QC on individuals for missingness, genderThis chapter is a comprehensive review of quality control (QC) methods for SNP-based genotyping panels used in genome-wide association studies. These include QC on individuals for missingness, gender checks, duplicates and cryptic relatedness, population outliers, heterozygosity and inbreeding, and QC on SNPs for missingness, minor allele frequency and Hardy-Weinberg equilibrium. The emphasis is on the reasons behind each QC step and on the use of intelligent approaches rather than arbitrary QC thresholds. Scripts and code for performing these QC steps are available at www.kcl.ac.uk/mmg/gwascode/ .

• A Genome-wide Study of Common SNPs and CNVs in Cognitive Performance in the CANTAB battery.

  Authors: Anna C Need, Deborah K Attix, Jill M McEvoy, Elizabeth T Cirulli, Kristen L. Linney, Priscilla Hunt, Dongliang Ge, Erin L Heinzen, Jessica M Maia, Kevin V Shianna, Michael E Weale, Lynn F Cherkas, Gail Clement, Tim D Spector, Greg Gibson, David B Goldstein

  Human molecular genetics. 10/2009;

  Psychiatric disorders such as schizophrenia are commonly accompanied by cognitive impairments that are treatment resistant and crucial to functional outcome. There has been great interest in studyingPsychiatric disorders such as schizophrenia are commonly accompanied by cognitive impairments that are treatment resistant and crucial to functional outcome. There has been great interest in studying cognitive measures as endophenotypes for psychiatric disorders, with the hope that their genetic basis will be clearer. To investigate this, we performed a genome-wide association study involving 11 cognitive phenotypes from the CANTAB battery. We showed these measures to be heritable by comparing the correlation in 100 monozygotic and 100 dizygotic twin pairs. The full battery was tested in approximately 750 subjects, and for spatial and verbal recognition memory (SRM and VRM), we investigated a further 500 individuals to search for smaller genetic effects. We were unable to find any genome-wide significant associations with either SNPs or common copy number variants (CNVs). Nor could we formally replicate any polymorphism that has been previously associated with cognition, although we found a weak signal of lower-than-expected p values for variants in a set of 10 candidate genes. We additionally investigated SNPs in genomic loci that have been shown to harbor rare variants that associate with neuropsychiatric disorders, to see if they showed any suggestion of association when considered as a separate set. Only NRXN1 showed evidence of significant association with cognition. These results suggest that common genetic variation does not strongly influence cognition in healthy subjects and that cognitive measures do not represent a more tractable genetic trait than clinical endpoints such as schizophrenia. We discuss a possible role for rare variation in cognitive genomics.

• Genomics software: The view from 10,000 feet.

  Authors: Michael E Weale

  Human genomics. 10/2009; 4(1):56-8.

  The rate of change in genomics, and 'omics generally, shows no signs of slowing down. Related analysis software is struggling to keep apace. This paper provides a brief review of the field.

• A genome-wide investigation of SNPs and CNVs in schizophrenia.

  Authors: Anna C Need, Dongliang Ge, Michael E Weale, Jessica Maia, Sheng Feng, Erin L Heinzen, Kevin V Shianna, Woohyun Yoon, Dalia Kasperaviciūte, Massimo Gennarelli [......] Gillian Fraser, Caroline Crombie, Lefkos T Middleton, David St Clair, Allen D Roses, Pierandrea Muglia, Clyde Francks, Dan Rujescu, Herbert Y Meltzer, David B Goldstein

  PLoS genetics. 02/2009; 5(2):e1000373.

  We report a genome-wide assessment of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) in schizophrenia. We investigated SNPs using 871 patients and 863 controls, following upWe report a genome-wide assessment of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) in schizophrenia. We investigated SNPs using 871 patients and 863 controls, following up the top hits in four independent cohorts comprising 1,460 patients and 12,995 controls, all of European origin. We found no genome-wide significant associations, nor could we provide support for any previously reported candidate gene or genome-wide associations. We went on to examine CNVs using a subset of 1,013 cases and 1,084 controls of European ancestry, and a further set of 60 cases and 64 controls of African ancestry. We found that eight cases and zero controls carried deletions greater than 2 Mb, of which two, at 8p22 and 16p13.11-p12.4, are newly reported here. A further evaluation of 1,378 controls identified no deletions greater than 2 Mb, suggesting a high prior probability of disease involvement when such deletions are observed in cases. We also provide further evidence for some smaller, previously reported, schizophrenia-associated CNVs, such as those in NRXN1 and APBA2. We could not provide strong support for the hypothesis that schizophrenia patients have a significantly greater "load" of large (>100 kb), rare CNVs, nor could we find common CNVs that associate with schizophrenia. Finally, we did not provide support for the suggestion that schizophrenia-associated CNVs may preferentially disrupt genes in neurodevelopmental pathways. Collectively, these analyses provide the first integrated study of SNPs and CNVs in schizophrenia and support the emerging view that rare deleterious variants may be more important in schizophrenia predisposition than common polymorphisms. While our analyses do not suggest that implicated CNVs impinge on particular key pathways, we do support the contribution of specific genomic regions in schizophrenia, presumably due to recurrent mutation. On balance, these data suggest that very few schizophrenia patients share identical genomic causation, potentially complicating efforts to personalize treatment regimens.

• A critical evaluation of genomic control methods for genetic association studies.

  Authors: Tony Dadd, Michael E Weale, Cathryn M Lewis

  Genetic epidemiology. 01/2009;

  Population stratification is an important potential confounder of genetic case-control association studies. For replication studies, limited availability of samples may lead to imbalanced samplingPopulation stratification is an important potential confounder of genetic case-control association studies. For replication studies, limited availability of samples may lead to imbalanced sampling from heterogeneous populations. Genomic control (GC) can be used to correct chi(2) test statistics which are presumed to be inflated by a factor lambda; this may be estimated by a summary chi(2) value (lambda(median) or lambda(mean)) from a set of unlinked markers. Many studies applying GC methods have used fewer than 50 unlinked markers and an important question is whether this can adequately correct for population stratification. We assess the behavior of GC methods in imbalanced case-control studies using simulation. SNPs are sampled from two subpopulations with intra-continental levels of FST (</=0.005) and sampling schemata ranging from balanced to completely imbalanced between subpopulations. The sampling properties of lambda(median) and lambda(mean) are explored using 6-1,600 unlinked markers to estimate Type 1 error and power empirically. GC corrections based on the chi(2)-distribution (GC(median) or GC(mean)) can be anti-conservative even when more than 100 single nucleotide polymorphisms (SNPs) are genotyped and realistic levels of population stratification exist. The GCF procedure performs well over a wider range of conditions, only becoming anti-conservative at low levels of alpha and with fewer than 25 SNPs genotyped. A substantial loss of power can arise when population stratification is present, but this is largely independent of the number of SNPs used. A literature survey shows that most studies applying GC have used GC(median) or GC(mean), rather than GCF, which is the most appropriate GC correction method. Genet. Epidemiol. 2008. (c) 2008 Wiley Liss, Inc.

• Sex-Specific Genetic Data Support One of Two Alternative Versions of the Foundation of the Ruling Dynasty of the Nso' in Cameroon.

  Authors: Krishna R Veeramah, David Zeitlyn, Verkijika G Fanso, Nancy R Mendell, Bruce A Connell, Michael E Weale, Neil Bradman, Mark G Thomas

  Current anthropology. 09/2008; 49(4):707-714.

  Sex-specific genetic data favor a specific variant of the oral history of the kingdom of Nso' (a Grassfields city-state in Cameroon) in which the royal family traces its descent from a foundingSex-specific genetic data favor a specific variant of the oral history of the kingdom of Nso' (a Grassfields city-state in Cameroon) in which the royal family traces its descent from a founding ancestress who married into an autochthonous hunter-gatherer group. The distributions of Y chromosome and mitochondrial DNA variation in the Nso' in general and in the ruling dynasty in particular are consistent with specific Nso' marriage practices, suggesting strict conservation of the royal social class along agnatic lines. This study demonstrates the efficacy of using genetics to augment other sources of information (e.g., oral histories, archaeology, and linguistics) when seeking to recover the histories of African peoples.

• Long-range LD can confound genome scans in admixed populations.

  Authors: Alkes L Price, Michael E Weale, Nick Patterson, Simon R Myers, Anna C Need, Kevin V Shianna, Dongliang Ge, Jerome I Rotter, Esther Torres, Kent D Taylor, David B Goldstein, David Reich

  American journal of human genetics. 08/2008; 83(1):132-5; author reply 135-9.

• An assessment of the Irish population for large-scale genetic mapping studies involving epilepsy and other complex diseases.

  Authors: Colm T O'Dushlaine, Ciara Dolan, Michael E Weale, Alice Stanton, David T Croke, Reetta Kalviainen, Kai Eriksson, Anne-Mari Kantanen, Rachel A Gibson, David Hosford, Sanjay M Sisodiya, Michael Gill, Aiden P Corvin, Derek W Morris, Norman Delanty, Gianpiero L Cavalleri

  European journal of human genetics : EJHG. 03/2008; 16(2):176-83.

  The recent completion of the International HapMap Project has rapidly advanced our understanding of linkage disequilibrium (LD) in the human genome. Today, tagging SNPs (tSNPs) can be quickly andThe recent completion of the International HapMap Project has rapidly advanced our understanding of linkage disequilibrium (LD) in the human genome. Today, tagging SNPs (tSNPs) can be quickly and easily selected and consequently HapMap data are regularly applied to both small- and large-scale genetic mapping studies. However, to correctly interpret the application of HapMap-derived tSNPs in a genetic mapping study, an understanding of how well HapMap data represents LD in the study population is critical. The Irish population had not previously been characterised in this way. Here, we do so using a set of 4424 SNPs selected from 279 candidate genes for epilepsy genotyped across 1118 healthy individuals from the Irish, British, Finnish and Australian populations. By considering the Irish population alongside surrounding European populations, our results confirm that the HapMap European-derived population accurately estimates patterning of LD in European descent populations. The Irish population appears notably well matched to the European HapMap population, and is markedly similar to the neighbouring British population. Although we were unable to detect significant substructure within the Irish population (a favourable result for genetic mapping), methods for controlling stratification should always be incorporated. This analysis therefore confirms that the genetic architecture of the Irish population is well suited to the study of complex traits and that tSNPs selected using the HapMap data can be confidently applied to the Irish population.