The future of association studies: gene-based analysis and replication.
paper
Cited
Public
Unavailable
- Authors
- Neale, Benjamin M; Sham, Pak C
- Year
- 2004
- Journal
- American journal of human genetics
- PMID
- 15272419
- DOI
- 10.1086/423901
- PMCID
- PMC1182015
Historically, association tests were limited to single variants, so that the allele was considered the basic unit for association testing. As marker density increases and indirect approaches are used to assess association through linkage disequilibrium, association is now frequently considered at the haplotypic level. We suggest that there are difficulties in replicating association findings at the single-nucleotide-polymorphism (SNP) or the haplotype level, and we propose a shift toward a gene-based approach in which all common variation within a candidate gene is considered jointly. Inconsistencies arising from population differences are more readily resolved by use of a gene-based approach rather than either a SNP-based or a haplotype-based approach. A gene-based approach captures all of the potential risk-conferring variations; thus, negative findings are subject only to the issue of power. In addition, chance findings due to multiple testing can be readily accounted for by use of a genewide-significance level. Meta-analysis procedures can be formalized for gene-based methods through the combination of P values. It is only a matter of time before all variation within genes is mapped, at which point the gene-based approach will become the natural end point for association analysis and will inform our search for functional variants relevant to disease etiology.
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| CLOCK may predict the response to fluvoxamine treatment in Japanese major depressive disorder patients. | Kishi T et al. | β | 2009 | β |
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| No evidence for association between the renin-angiotensin-aldosterone system and otosclerosis in a large Belgian-Dutch population. | Schrauwen I et al. | β | 2009 | β |
| Overview on the current status of asthma genetics. | Halapi E et al. | β | 2009 | β |
| Promoter polymorphism of matrilin-1 gene predisposes to adolescent idiopathic scoliosis in a Chinese population. | Chen Z et al. | β | 2009 | β |
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| Targeted resequencing and analysis of the Diamond-Blackfan anemia disease locus RPS19. | Martinez Barrio A et al. | β | 2009 | β |
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| AKT1 is associated with schizophrenia across multiple symptom dimensions in the Irish study of high density schizophrenia families. | Thiselton DL et al. | β | 2008 | β |
| A quality assessment of genetic association studies supporting susceptibility and outcome in acute lung injury. | Flores C et al. | β | 2008 | β |
| A simple method for assessing the strength of evidence for association at the level of the whole gene. | Curtis D et al. | β | 2008 | β |
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| Association between tryptophan hydroxylase 2, performance on a continuance performance test and response to methylphenidate in ADHD participants. | Manor I et al. | β | 2008 | β |
| Association of bone morphogenetic proteins with otosclerosis. | Schrauwen I et al. | β | 2008 | β |
| Association of polymorphisms in NOS3 with the ankle-brachial index in hypertensive adults. | Kullo IJ et al. | β | 2008 | β |
| Association of the SLC45A2 gene with physiological human hair colour variation. | Branicki W et al. | β | 2008 | β |
| Association study between the Down syndrome cell adhesion molecule (DSCAM) gene and bipolar disorder. | Amano K et al. | β | 2008 | β |
| Association study of CSF2RB with schizophrenia in Irish family and case - control samples. | Chen Q et al. | β | 2008 | β |
| Association study of interleukin 2 (IL2) and IL4 with schizophrenia in a Japanese population. | Watanabe Y et al. | β | 2008 | β |
| A systematic search for SNPs/haplotypes associated with disease phenotypes using a haplotype-based stepwise procedure. | Yang Y et al. | β | 2008 | β |
| Cannabinoid receptor 1 gene association with nicotine dependence. | Chen X et al. | β | 2008 | β |
| Common variation in the fat mass and obesity-associated (FTO) gene confers risk of obesity and modulates BMI in the Chinese population. | Chang YC et al. | β | 2008 | β |
| Discovering susceptibility genes for asthma and allergy. | Vercelli D | β | 2008 | β |
| Dysbindin (DTNBP1) and the biogenesis of lysosome-related organelles complex 1 (BLOC-1): main and epistatic gene effects are potential contributors to schizophrenia susceptibility. | Morris DW et al. | β | 2008 | β |
| Endothelial nitric oxide synthase gene haplotypes and diabetic nephropathy among Asian Indians. | Ahluwalia TS et al. | β | 2008 | β |
| Experimental therapeutics for refractory obsessive-compulsive disorder: translational approaches and new somatic developments. | Berlin HA et al. | β | 2008 | β |
| Failure to replicate the association between NRG1 and schizophrenia using Japanese large sample. | Ikeda M et al. | β | 2008 | β |
| FBXL21 association with schizophrenia in Irish family and case-control samples. | Chen X et al. | β | 2008 | β |
| Gene-centric genomewide association study via entropy. | Cui Y et al. | β | 2008 | β |
| Gene expression in the etiology of schizophrenia. | Bray NJ | β | 2008 | β |
| Genetic association analysis of tagging SNPs in alpha4 and beta2 subunits of neuronal nicotinic acetylcholine receptor genes (CHRNA4 and CHRNB2) with schizophrenia in the Japanese population. | Kishi T et al. | β | 2008 | β |
| Genetic association studies of neurotensin gene and restless legs syndrome in French Canadians. | Xiong L et al. | β | 2008 | β |
| Group additive regression models for genomic data analysis. | Luan Y et al. | β | 2008 | β |
| How the serotonin story is being rewritten by new gene-based discoveries principally related to SLC6A4, the serotonin transporter gene, which functions to influence all cellular serotonin systems. | Murphy DL et al. | β | 2008 | β |
| IL6 gene-wide haplotype is associated with susceptibility to acute lung injury. | Flores C et al. | β | 2008 | β |
| Impact of matrix metalloproteinase-1 gene variations on risk of acute coronary syndrome. | Han Y et al. | β | 2008 | β |
| Individual differences in allocation of funds in the dictator game associated with length of the arginine vasopressin 1a receptor RS3 promoter region and correlation between RS3 length and hippocampal mRNA. | Knafo A et al. | β | 2008 | β |
| Interaction between interleukin 3 and dystrobrevin-binding protein 1 in schizophrenia. | Edwards TL et al. | β | 2008 | β |
| Macrophage migration inhibitory factor and autism spectrum disorders. | Grigorenko EL et al. | β | 2008 | β |
| MEGF10 association with schizophrenia. | Chen X et al. | β | 2008 | β |
| Myosin light chain kinase gene and acute lung injury in trauma and sepsis: opposite effects but confirmatory. | Gong MN | β | 2008 | β |
| Neuregulin 1 genotype and schizophrenia. | MunafΓ² MR et al. | β | 2008 | β |
| No association between prostate apoptosis response 4 gene (PAWR) in schizophrenia and mood disorders in a Japanese population. | Kishi T et al. | β | 2008 | β |
| No association between tagging SNPs of SNARE complex genes (STX1A, VAMP2 and SNAP25) and schizophrenia in a Japanese population. | Kawashima K et al. | β | 2008 | β |
| No association between the oligodendrocyte-related gene PLP1 and schizophrenia in the Japanese population. | Aleksic B et al. | β | 2008 | β |
| No association between the protein tyrosine phosphatase, receptor-type, Z Polypeptide 1 (PTPRZ1) gene and schizophrenia in the Japanese population. | Ito Y et al. | β | 2008 | β |
| Perspective on the genetics of attention deficit/hyperactivity disorder. | Neale BM et al. | β | 2008 | β |
| Pharmacogenetic analysis of genes implicated in rodent models of antidepressant response: association of TREK1 and treatment resistance in the STAR(*)D study. | Perlis RH et al. | β | 2008 | β |
| Preliminary evidence that specific candidate genes are associated with adolescent-onset antisocial behavior. | Burt SA et al. | β | 2008 | β |
| Prostasin: a possible candidate gene for human hypertension. | Zhu H et al. | β | 2008 | β |
| Prostate apoptosis response 4 gene is not associated with methamphetamine-use disorder in the Japanese population. | Kishi T et al. | β | 2008 | β |
| Selecting predictive markers for pharmacogenetic traits: tagging vs. data-mining approaches. | Sabbagh A et al. | β | 2008 | β |
| The nature of nurture: a genomewide association scan for family chaos. | Butcher LM et al. | β | 2008 | β |
| Trends in meta-analysis of genetic association studies. | Zintzaras E et al. | β | 2008 | β |
| Use of association studies to define genetic modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers. | Hughes DJ | β | 2008 | β |
| U-statistics-based tests for multiple genes in genetic association studies. | Wei Z et al. | β | 2008 | β |
| Variants in the neuronal nitric oxide synthase (nNOS, NOS1) gene are associated with restless legs syndrome. | Winkelmann J et al. | β | 2008 | β |
| Worldwide distribution of NAT2 diversity: implications for NAT2 evolutionary history. | Sabbagh A et al. | β | 2008 | β |
| A generic research paradigm for identification and validation of early molecular diagnostics and new therapeutics in common disorders. | Coon KD et al. | β | 2007 | β |
| A novel intronic polymorphism of ABCA1 gene reveals risk for sporadic Alzheimer's disease in Chinese. | Chu LW et al. | β | 2007 | β |
| Applicability of DNA pools on 500 K SNP microarrays for cost-effective initial screens in genomewide association studies. | Docherty SJ et al. | β | 2007 | β |
| A region of 35 kb containing the trace amine associate receptor 6 (TAAR6) gene is associated with schizophrenia in the Irish study of high-density schizophrenia families. | Vladimirov V et al. | β | 2007 | β |
| Association between obsessive-compulsive disorder and a variable number of tandem repeats polymorphism in intron 2 of the serotonin transporter gene. | Baca-Garcia E et al. | β | 2007 | β |
| Association between variations in CAT and noise-induced hearing loss in two independent noise-exposed populations. | Konings A et al. | β | 2007 | β |
| Association of urokinase-type plasminogen activator with asthma and atopy. | BΓ©gin P et al. | β | 2007 | β |
| Comment on: Chang et al. (2007) Association study of the genetic polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene and type 2 diabetes in the Chinese population: Diabetes 56:2631-2637. | Ku CS et al. | β | 2007 | β |
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| Evaluation of genome-wide power of genetic association studies based on empirical data from the HapMap project. | Nannya Y et al. | β | 2007 | β |
| Evidence for association and epistasis at the DAOA/G30 and D-amino acid oxidase loci in an Irish schizophrenia sample. | Corvin A et al. | β | 2007 | β |
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| Genetics in psychosomatic medicine: research designs and statistical approaches. | McCaffery JM et al. | β | 2007 | β |
| Interleukin 3 and schizophrenia: the impact of sex and family history. | Chen X et al. | β | 2007 | β |
| Is COMT a susceptibility gene for schizophrenia? | Williams HJ et al. | β | 2007 | β |
| Multilocus analyses of Renin-Angiotensin-aldosterone system gene variants on blood pressure at rest and during behavioral stress in young normotensive subjects. | Ge D et al. | β | 2007 | β |
| No association between the BDNF Val66Met polymorphism and mood status in a non-clinical community sample of 7389 older adults. | Surtees PG et al. | β | 2007 | β |
| No association between the glutamate decarboxylase 67 gene (GAD1) and schizophrenia in the Japanese population. | Ikeda M et al. | β | 2007 | β |
| No association of chromatin-modifying protein 2B with sporadic frontotemporal dementia. | Schumacher A et al. | β | 2007 | β |
| No association of vacuolar protein sorting 26 polymorphisms with Alzheimer's disease. | Riemenschneider M et al. | β | 2007 | β |
| Polymorphisms in NACHT-LRR (NLR) genes in atopic dermatitis. | Macaluso F et al. | β | 2007 | β |
| Regulatory polymorphisms in the cyclophilin A gene, PPIA, accelerate progression to AIDS. | An P et al. | β | 2007 | β |
| Replicating genotype-phenotype associations. | NCI-NHGRI Working Group on Replication in Association Studies et al. | β | 2007 | β |
| Signatures of recent positive selection at the ATP-binding cassette drug transporter superfamily gene loci. | Wang Z et al. | β | 2007 | β |
| The impact of a TSH receptor gene polymorphism on thyroid-related phenotypes in a healthy Danish twin population. | Hansen PS et al. | β | 2007 | β |
| Toward a comprehensive set of asthma susceptibility genes. | BossΓ© Y et al. | β | 2007 | β |
| Tumour necrosis factor and lymphotoxin A polymorphisms and lung function in smokers. | Tanaka G et al. | β | 2007 | β |
| Weak independent association signals between IDE polymorphisms, Alzheimer's disease and cognitive measures. | Mueller JC et al. | β | 2007 | β |
| ABCB1/MDR1 gene determines susceptibility and phenotype in ulcerative colitis: discrimination of critical variants using a gene-wide haplotype tagging approach. | Ho GT et al. | β | 2006 | β |
| A genome-wide scan and HCRTR2 candidate gene analysis in a European cluster headache cohort. | Baumber L et al. | β | 2006 | β |
| AMP-kinase alpha2 subunit gene PRKAA2 variants are associated with total cholesterol, low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol in normal women. | Spencer-Jones NJ et al. | β | 2006 | β |
| A relook into the association of the estrogen receptor [alpha] gene (PvuII, XbaI) and adolescent idiopathic scoliosis: a study of 540 Chinese cases. | Tang NL et al. | β | 2006 | β |
| A scan statistic for identifying chromosomal patterns of SNP association. | Sun YV et al. | β | 2006 | β |
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| Concordant association of lipid gene variation with a combined HDL/LDL-cholesterol phenotype in two European populations. | Bauerfeind A et al. | β | 2006 | β |
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| Dissecting complex disease: the quest for the Philosopher's Stone? | Buchanan AV et al. | β | 2006 | β |
| ERCC4 associated with breast cancer risk: a two-stage case-control study using high-throughput genotyping. | Milne RL et al. | β | 2006 | β |
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| G72/G30 in schizophrenia and bipolar disorder: review and meta-analysis. | Detera-Wadleigh SD et al. | β | 2006 | β |
| Gene-based analysis suggests association of the nicotinic acetylcholine receptor beta1 subunit (CHRNB1) and M1 muscarinic acetylcholine receptor (CHRM1) with vulnerability for nicotine dependence. | Lou XY et al. | β | 2006 | β |
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| Investigating the genetic determinants of cardiovascular disease using candidate genes and meta-analysis of association studies. | Casas JP et al. | β | 2006 | β |
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| Molecular genetic studies of gene identification for osteoporosis: a 2004 update. | Liu YJ et al. | β | 2006 | β |
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| Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application. | Millan MJ | β | 2006 | β |
| Nonlinear tests for genomewide association studies. | Zhao J et al. | β | 2006 | β |
| Phosphatidylinositol 3-kinase p85alpha regulatory subunit gene PIK3R1 haplotype is associated with body fat and serum leptin in a female twin population. | Jamshidi Y et al. | β | 2006 | β |
| Plasminogen activator inhibitor-1 gene: selection of tagging single nucleotide polymorphisms and association with coronary heart disease. | Su S et al. | β | 2006 | β |
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| Regulatory cytokine gene polymorphisms and risk of colorectal carcinoma. | Crivello A et al. | β | 2006 | β |
| Replication of IGF2-INS-TH*5 haplotype effect on obesity in older men and study of related phenotypes. | RodrΓguez S et al. | β | 2006 | β |
| Resampling-based multiple hypothesis testing procedures for genetic case-control association studies. | Chen BE et al. | β | 2006 | β |
| Serious carbamazepine-induced hypersensitivity reactions associated with the HSP70 gene cluster. | Alfirevic A et al. | β | 2006 | β |
| Systematic replication study of reported genetic associations in prostate cancer: Strong support for genetic variation in the androgen pathway. | LindstrΓΆm S et al. | β | 2006 | β |
| The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes. | Brookes K et al. | β | 2006 | β |
| The catechol-O-methyl transferase (COMT) gene as a candidate for psychiatric phenotypes: evidence and lessons. | Craddock N et al. | β | 2006 | β |
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| The current status of association studies in obsessive-compulsive disorder. | Hemmings SM et al. | β | 2006 | β |
| The future of epidemiology: methodological challenges and multilevel inference. | Duell EJ | β | 2006 | β |
| The genetics of depression: a review. | Levinson DF | β | 2006 | β |
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| When is a replication not a replication? Or how to spot a good genetic association study. | Spector TD et al. | β | 2006 | β |
| A genetic variant in the gene encoding the stress70 protein chaperone family member STCH is associated with gastric cancer in the Japanese population. | Aoki M et al. | β | 2005 | β |
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| APOC3/A5 haplotypes, lipid levels, and risk of myocardial infarction in the Central Valley of Costa Rica. | Ruiz-NarvΓ‘ez EA et al. | β | 2005 | β |
| Applications of whole-genome high-density SNP genotyping. | Craig DW et al. | β | 2005 | β |
| Association analysis of the Arg220His variation of the human gene encoding the GABA delta subunit with idiopathic generalized epilepsy. | Lenzen KP et al. | β | 2005 | β |
| AVPR1a and SLC6A4 gene polymorphisms are associated with creative dance performance. | Bachner-Melman R et al. | β | 2005 | β |
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