Family-based association tests for genomewide association scans.
paper
Cited
Public
Unavailable
- Authors
- Chen, Wei-Min; Abecasis, Goncalo R
- Year
- 2007
- Journal
- American journal of human genetics
- PMID
- 17924335
- DOI
- 10.1086/521580
- PMCID
- PMC2265659
With millions of single-nucleotide polymorphisms (SNPs) identified and characterized, genomewide association studies have begun to identify susceptibility genes for complex traits and diseases. These studies involve the characterization and analysis of very-high-resolution SNP genotype data for hundreds or thousands of individuals. We describe a computationally efficient approach to testing association between SNPs and quantitative phenotypes, which can be applied to whole-genome association scans. In addition to observed genotypes, our approach allows estimation of missing genotypes, resulting in substantial increases in power when genotyping resources are limited. We estimate missing genotypes probabilistically using the Lander-Green or Elston-Stewart algorithms and combine high-resolution SNP genotypes for a subset of individuals in each pedigree with sparser marker data for the remaining individuals. We show that power is increased whenever phenotype information for ungenotyped individuals is included in analyses and that high-density genotyping of just three carefully selected individuals in a nuclear family can recover >90% of the information available if every individual were genotyped, for a fraction of the cost and experimental effort. To aid in study design, we evaluate the power of strategies that genotype different subsets of individuals in each pedigree and make recommendations about which individuals should be genotyped at a high density. To illustrate our method, we performed genomewide association analysis for 27 gene-expression phenotypes in 3-generation families (Centre d'Etude du Polymorphisme Humain pedigrees), in which genotypes for ~860,000 SNPs in 90 grandparents and parents are complemented by genotypes for ~6,700 SNPs in a total of 168 individuals. In addition to increasing the evidence of association at 15 previously identified cis-acting associated alleles, our genotype-inference algorithm allowed us to identify associated alleles at 4 cis-acting loci that were missed when analysis was restricted to individuals with the high-density SNP data. Our genotype-inference algorithm and the proposed association tests are implemented in software that is available for free.
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| Incorporating genotype uncertainties into the genotypic TDT for main effects and gene-environment interactions. | Taub MA et al. | β | 2012 | β |
| Integrating pathway analysis and genetics of gene expression for genome-wide association study of basal cell carcinoma. | Zhang M et al. | β | 2012 | β |
| Localising loci underlying complex trait variation using Regional Genomic Relationship Mapping. | Nagamine Y et al. | β | 2012 | β |
| Loci affecting gamma-glutamyl transferase in adults and adolescents show age Γ SNP interaction and cardiometabolic disease associations. | Middelberg RP et al. | β | 2012 | β |
| Low-frequency variants in HMGA1 are not associated with type 2 diabetes risk. | Marquez M et al. | β | 2012 | β |
| Mapping cis- and trans-regulatory effects across multiple tissues in twins. | Grundberg E et al. | β | 2012 | β |
| Meta-analysis of genome-wide association studies for personality. | de Moor MH et al. | β | 2012 | β |
| No association of candidate genes with cannabis use in a large sample of Australian twin families. | Verweij KJ et al. | β | 2012 | β |
| On the meta-analysis of genome-wide association studies: a robust and efficient approach to combine population and family-based studies. | Won S et al. | β | 2012 | β |
| Population structure of Hispanics in the United States: the multi-ethnic study of atherosclerosis. | Manichaikul A et al. | β | 2012 | β |
| Rapid variance components-based method for whole-genome association analysis. | Svishcheva GR et al. | β | 2012 | β |
| Statistical distributions of test statistics used for quantitative trait association mapping in structured populations. | TeyssΓ¨dre S et al. | β | 2012 | β |
| The architecture of long-range haplotypes shared within and across populations. | Gusev A et al. | β | 2012 | β |
| The Brisbane Systems Genetics Study: genetical genomics meets complex trait genetics. | Powell JE et al. | β | 2012 | β |
| The robustness of generalized estimating equations for association tests in extended family data. | Suktitipat B et al. | β | 2012 | β |
| Uncovering networks from genome-wide association studies via circular genomic permutation. | Cabrera CP et al. | β | 2012 | β |
| Using family-based imputation in genome-wide association studies with large complex pedigrees: the Framingham Heart Study. | Chen MH et al. | β | 2012 | β |
| A flexible model for association analysis in sibships with missing genotype data. | Dudbridge F et al. | β | 2011 | β |
| A quantitative-trait genome-wide association study of alcoholism risk in the community: findings and implications. | Heath AC et al. | β | 2011 | β |
| A rapid generalized least squares model for a genome-wide quantitative trait association analysis in families. | Li X et al. | β | 2011 | β |
| A strategy analysis for genetic association studies with known inbreeding. | Cabras S et al. | β | 2011 | β |
| Common polymorphisms in the GH/IGF-1 axis contribute to growth in extremely tall subjects. | Hendriks AE et al. | β | 2011 | β |
| Educational attainment: a genome wide association study in 9538 Australians. | Martin NW et al. | β | 2011 | β |
| Estimating myostatin gene effect on milk performance traits using estimated gene content for a large number of non-genotyped cows. | Buske B et al. | β | 2011 | β |
| Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. | Sanna S et al. | β | 2011 | β |
| Genetic predictors of fibrin D-dimer levels in healthy adults. | Smith NL et al. | β | 2011 | β |
| Genetic variance in a component of the language acquisition device: ROBO1 polymorphisms associated with phonological buffer deficits. | Bates TC et al. | β | 2011 | β |
| Genome-wide association analysis and fine mapping of NT-proBNP level provide novel insight into the role of the MTHFR-CLCN6-NPPA-NPPB gene cluster. | Del Greco M F et al. | β | 2011 | β |
| Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2. | Wright FA et al. | β | 2011 | β |
| Genome-wide association study identifies five loci associated with susceptibility to pancreatic cancer in Chinese populations. | Wu C et al. | β | 2011 | β |
| GWAS findings for human iris patterns: associations with variants in genes that influence normal neuronal pattern development. | Larsson M et al. | β | 2011 | β |
| GWAS of butyrylcholinesterase activity identifies four novel loci, independent effects within BCHE and secondary associations with metabolic risk factors. | Benyamin B et al. | β | 2011 | β |
| Haplotypes versus genotypes on pedigrees. | Kirkpatrick BB | β | 2011 | β |
| Identification of a sudden cardiac death susceptibility locus at 2q24.2 through genome-wide association in European ancestry individuals. | Arking DE et al. | β | 2011 | β |
| Identifying variants that contribute to linkage for dichotomous and quantitative traits in extended pedigrees. | Chen WM et al. | β | 2011 | β |
| Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels. | Dehghan A et al. | β | 2011 | β |
| Perspectives on genome-wide multi-stage family-based association studies. | Van Steen K | β | 2011 | β |
| Polymorphisms in B3GAT1, SLC9A9 and MGAT5 are associated with variation within the human plasma N-glycome of 3533 European adults. | Huffman JE et al. | β | 2011 | β |
| SNP sets and reading ability: testing confirmation of a 10-SNP set in a population sample. | Luciano M et al. | β | 2011 | β |
| A genome-wide association study of Cloninger's temperament scales: implications for the evolutionary genetics of personality. | Verweij KJ et al. | β | 2010 | β |
| A genome-wide association study of neuroticism in a population-based sample. | Calboli FC et al. | β | 2010 | β |
| A genome-wide association study of optic disc parameters. | Ramdas WD et al. | β | 2010 | β |
| A genome-wide association study of self-rated health. | Mosing MA et al. | β | 2010 | β |
| A locus on chromosome 1p36 is associated with thyrotropin and thyroid function as identified by genome-wide association study. | Panicker V et al. | β | 2010 | β |
| A meta-analysis of genome-wide data from five European isolates reveals an association of COL22A1, SYT1, and GABRR2 with serum creatinine level. | Pattaro C et al. | β | 2010 | β |
| An alternative to the search for single polymorphisms: toward molecular personality scales for the five-factor model. | McCrae RR et al. | β | 2010 | β |
| Association of matrix metalloproteinase gene polymorphisms with refractive error in Amish and Ashkenazi families. | Wojciechowski R et al. | β | 2010 | β |
| BDNF Val66Met is associated with introversion and interacts with 5-HTTLPR to influence neuroticism. | Terracciano A et al. | β | 2010 | β |
| Common genetic determinants of vitamin D insufficiency: a genome-wide association study. | Wang TJ et al. | β | 2010 | β |
| Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction. | Sotoodehnia N et al. | β | 2010 | β |
| Gene expression in skin and lymphoblastoid cells: Refined statistical method reveals extensive overlap in cis-eQTL signals. | Ding J et al. | β | 2010 | β |
| Genetic variation of DKK3 may modify renal disease severity in ADPKD. | Liu M et al. | β | 2010 | β |
| Genome-wide association scan for five major dimensions of personality. | Terracciano A et al. | β | 2010 | β |
| Genome-wide association scan of trait depression. | Terracciano A et al. | β | 2010 | β |
| Genomic approaches to coronary artery disease. | Padmanabhan S et al. | β | 2010 | β |
| Genomics meets glycomics-the first GWAS study of human N-Glycome identifies HNF1Ξ± as a master regulator of plasma protein fucosylation. | Lauc G et al. | β | 2010 | β |
| Haplotype inference in complex pedigrees. | Kirkpatrick B et al. | β | 2010 | β |
| IRF4 variants have age-specific effects on nevus count and predispose to melanoma. | Duffy DL et al. | β | 2010 | β |
| Linkage and genome-wide association analysis of obesity-related phenotypes: association of weight with the MGAT1 gene. | Johansson A et al. | β | 2010 | β |
| Magnitude of stratification in human populations and impacts on genome wide association studies. | Hao K et al. | β | 2010 | β |
| Modeling of environmental effects in genome-wide association studies identifies SLC2A2 and HP as novel loci influencing serum cholesterol levels. | Igl W et al. | β | 2010 | β |
| New loci associated with central cornea thickness include COL5A1, AKAP13 and AVGR8. | Vitart V et al. | β | 2010 | β |
| ProbABEL package for genome-wide association analysis of imputed data. | Aulchenko YS et al. | β | 2010 | β |
| Quantitative trait loci for CD4:CD8 lymphocyte ratio are associated with risk of type 1 diabetes and HIV-1 immune control. | Ferreira MA et al. | β | 2010 | β |
| Robust relationship inference in genome-wide association studies. | Manichaikul A et al. | β | 2010 | β |
| The perception of quinine taste intensity is associated with common genetic variants in a bitter receptor cluster on chromosome 12. | Reed DR et al. | β | 2010 | β |
| The TCF7L2 diabetes risk variant is associated with HbAβ(C) levels: a genome-wide association meta-analysis. | Franklin CS et al. | β | 2010 | β |
| Two-stage testing strategies for genome-wide association studies in family-based designs. | Murphy A et al. | β | 2010 | β |
| Variance component model to account for sample structure in genome-wide association studies. | Kang HM et al. | β | 2010 | β |
| A Fast Implementation of a Scan Statistic for Identifying Chromosomal Patterns of Genome Wide Association Studies. | Sun YV et al. | β | 2009 | β |
| A generalized family-based association test for dichotomous traits. | Chen WM et al. | β | 2009 | β |
| A genome-wide association study identifies a novel locus on chromosome 18q12.2 influencing white cell telomere length. | Mangino M et al. | β | 2009 | β |
| A kinship-based modification of the armitage trend test to address hidden population structure and small differential genotyping errors. | Rakovski CS et al. | β | 2009 | β |
| Association and interaction analyses of eight genes under asthma linkage peaks. | Ferreira MA et al. | β | 2009 | β |
| Association of regions on chromosomes 6 and 7 with blood pressure in Nigerian families. | Tayo BO et al. | β | 2009 | β |
| Association of TRPV4 gene polymorphisms with chronic obstructive pulmonary disease. | Zhu G et al. | β | 2009 | β |
| Bivariate association analyses for the mixture of continuous and binary traits with the use of extended generalized estimating equations. | Liu J et al. | β | 2009 | β |
| COL4A1 is associated with arterial stiffness by genome-wide association scan. | Tarasov KV et al. | β | 2009 | β |
| Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. | Lyssenko V et al. | β | 2009 | β |
| Common variants in the JAZF1 gene associated with height identified by linkage and genome-wide association analysis. | Johansson A et al. | β | 2009 | β |
| Common variants in the SLCO1B3 locus are associated with bilirubin levels and unconjugated hyperbilirubinemia. | Sanna S et al. | β | 2009 | β |
| Comparison between single-marker analysis using Merlin and multi-marker analysis using LASSO for Framingham simulated data. | Sung YJ et al. | β | 2009 | β |
| Correcting for relatedness in Bayesian models for genomic data association analysis. | Pikkuhookana P et al. | β | 2009 | β |
| Extended haplotypes in the growth hormone releasing hormone receptor gene (GHRHR) are associated with normal variation in height. | Johansson A et al. | β | 2009 | β |
| Family-based bivariate association tests for quantitative traits. | Zhang L et al. | β | 2009 | β |
| Family-based genome-wide association studies. | Benyamin B et al. | β | 2009 | β |
| Gene mapping in the wild with SNPs: guidelines and future directions. | Slate J et al. | β | 2009 | β |
| Genetic association tests: a method for the joint analysis of family and case-control data. | Gray-McGuire C et al. | β | 2009 | β |
| Genetic determinants of circulating sphingolipid concentrations in European populations. | Hicks AA et al. | β | 2009 | β |
| Genome-wide association studies and the genetic dissection of complex traits. | Sebastiani P et al. | β | 2009 | β |
| Genome-wide association study identifies variants at 9p21 and 22q13 associated with development of cutaneous nevi. | Falchi M et al. | β | 2009 | β |
| Genome-wide association study of anthropometric traits in Korcula Island, Croatia. | Polasek O et al. | β | 2009 | β |
| Genome-wide association study of biochemical traits in Korcula Island, Croatia. | Zemunik T et al. | β | 2009 | β |
| Genome-wide association study of plasma polyunsaturated fatty acids in the InCHIANTI Study. | Tanaka T et al. | β | 2009 | β |
| Genome-wide discovery of maternal effect variants. | Kent JW et al. | β | 2009 | β |
| Genotype imputation. | Li Y et al. | β | 2009 | β |
| GWAS GUI: graphical browser for the results of whole-genome association studies with high-dimensional phenotypes. | Chen W et al. | β | 2009 | β |
| Heritability and demographic analyses in the large isolated population of Val Borbera suggest advantages in mapping complex traits genes. | Traglia M et al. | β | 2009 | β |
| Maximizing the Power of Genome-Wide Association Studies: A Novel Class of Powerful Family-Based Association Tests. | Won S et al. | β | 2009 | β |
| Multistage analysis strategies for genome-wide association studies: summary of group 3 contributions to Genetic Analysis Workshop 16. | Neuman RJ et al. | β | 2009 | β |
| On the analysis of genome-wide association studies in family-based designs: a universal, robust analysis approach and an application to four genome-wide association studies. | Won S et al. | β | 2009 | β |
| Sequence variants in three loci influence monocyte counts and erythrocyte volume. | Ferreira MA et al. | β | 2009 | β |
| Single-nucleotide polymorphism bioinformatics: a comprehensive review of resources. | Johnson AD | β | 2009 | β |
| Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. | Willer CJ et al. | β | 2009 | β |
| STK39 polymorphisms and blood pressure: an association study in British Caucasians and assessment of cis-acting influences on gene expression. | Cunnington MS et al. | β | 2009 | β |
| Tests of association for quantitative traits in nuclear families using principal components to correct for population stratification. | Zhang L et al. | β | 2009 | β |
| Using new tools to define the genetic underpinnings of risky traits associated with coronary artery disease: the SardiNIA study. | Strait JB et al. | β | 2009 | β |
| Variants of the serotonin transporter gene and NEO-PI-R Neuroticism: No association in the BLSA and SardiNIA samples. | Terracciano A et al. | β | 2009 | β |
| Accounting for ancestry: population substructure and genome-wide association studies. | Tian C et al. | β | 2008 | β |
| Association of the dopamine transporter gene and ADHD symptoms in a Canadian population-based sample of same-age twins. | Ouellet-Morin I et al. | β | 2008 | β |
| Common variants in the GDF5-UQCC region are associated with variation in human height. | Sanna S et al. | β | 2008 | β |
| Common variants near MC4R are associated with fat mass, weight and risk of obesity. | Loos RJ et al. | β | 2008 | β |
| Comprehensive association study of type 2 diabetes and related quantitative traits with 222 candidate genes. | Gaulton KJ et al. | β | 2008 | β |
| Disease associations and family-based tests. | Ewens WJ et al. | β | 2008 | β |
| Genome-wide association studies for complex traits: consensus, uncertainty and challenges. | McCarthy MI et al. | β | 2008 | β |
| Genome-wide association studies of quantitative traits with related individuals: little (power) lost but much to be gained. | Visscher PM et al. | β | 2008 | β |
| Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and amelioration of the phenotype of beta-thalassemia. | Uda M et al. | β | 2008 | β |
| Genome-wide SNP-based linkage scan identifies a locus on 8q24 for an age-related hearing impairment trait. | Huyghe JR et al. | β | 2008 | β |
| Identification of ten loci associated with height highlights new biological pathways in human growth. | Lettre G et al. | β | 2008 | β |
| Newly identified loci that influence lipid concentrations and risk of coronary artery disease. | Willer CJ et al. | β | 2008 | β |
| Phosphodiesterase 8B gene variants are associated with serum TSH levels and thyroid function. | Arnaud-Lopez L et al. | β | 2008 | β |
| Replication of the Wellcome Trust genome-wide association study of essential hypertension: the Family Blood Pressure Program. | Ehret GB et al. | β | 2008 | β |
| Traceability of four European Protected Geographic Indication (PGI) beef products using Single Nucleotide Polymorphisms (SNP) and Bayesian statistics. | Negrini R et al. | β | 2008 | β |
| Variations in the G6PC2/ABCB11 genomic region are associated with fasting glucose levels. | Chen WM et al. | β | 2008 | β |
| Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. | Scuteri A et al. | β | 2007 | β |
| The GLUT9 gene is associated with serum uric acid levels in Sardinia and Chianti cohorts. | Li S et al. | β | 2007 | β |