Genome-Wide Association Studies: Progress in Identifying Genetic Biomarkers in Common, Complex Diseases

Novel, comprehensive approaches for biomarker discovery and validation are urgently needed. One particular area of methodologic need is for discovery of novel genetic biomarkers in complex diseases and traits. Here, we review recent successes in the use of genome wide association (GWA) approaches to identify genetic biomarkers in common human diseases and traits. Such studies are yielding initial insights into the allelic architecture of complex traits. In general, it appears that complex diseases are associated with many common polymorphisms, implying profound genetic heterogeneity between affected individuals.

[1]  S. Cichon,et al.  A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder , 2008, Molecular Psychiatry.

[2]  J. Downing,et al.  Genome-wide single-nucleotide polymorphism analysis in juvenile myelomonocytic leukemia identifies uniparental disomy surrounding the NF1 locus in cases associated with neurofibromatosis but not in cases with mutant RAS or PTPN11 , 2007, Oncogene.

[3]  C. Gieger,et al.  Association of variants in the BAT1-NFKBIL1-LTA genomic region with protection against myocardial infarction in Europeans. , 2007, Human molecular genetics.

[4]  D. Gudbjartsson,et al.  Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor–positive breast cancer , 2007, Nature Genetics.

[5]  Simon C. Potter,et al.  Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls , 2007, Nature.

[6]  Marcia M. Nizzari,et al.  Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels , 2007, Science.

[7]  M. McCarthy,et al.  Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes , 2007, Science.

[8]  Beverley Balkau,et al.  Variation in FTO contributes to childhood obesity and severe adult obesity , 2007, Nature Genetics.

[9]  J. Erdmann,et al.  Lymphotoxin-α and galectin-2 SNPs are not associated with myocardial infarction in two different German populations , 2007, Journal of Molecular Medicine.

[10]  P. Fearnhead,et al.  Genome-wide association study of prostate cancer identifies a second risk locus at 8q24 , 2007, Nature Genetics.

[11]  D. Gudbjartsson,et al.  Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24 , 2007, Nature Genetics.

[12]  Judy H Cho,et al.  Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis , 2007, Nature Genetics.

[13]  Christopher B. Miller,et al.  Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia , 2007, Nature.

[14]  A. Whittemore,et al.  Multiple regions within 8q24 independently affect risk for prostate cancer , 2007, Nature Genetics.

[15]  Simon Heath,et al.  Novel Crohn Disease Locus Identified by Genome-Wide Association Maps to a Gene Desert on 5p13.1 and Modulates Expression of PTGER4 , 2007, PLoS genetics.

[16]  A. Kimura,et al.  Lack of association between LTA and LGALS2 polymorphisms and myocardial infarction in Japanese and Korean populations. , 2007, Tissue antigens.

[17]  Thomas Lengauer,et al.  A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1 , 2007, Nature Genetics.

[18]  Judy H. Cho,et al.  A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene , 2006, Science.

[19]  Jason J. Corneveaux,et al.  Common Kibra Alleles Are Associated with Human Memory Performance , 2006, Science.

[20]  A. Gylfason,et al.  A common variant associated with prostate cancer in European and African populations , 2006, Nature Genetics.

[21]  Y. Ohnishi,et al.  Impact of atherosclerosis-related gene polymorphisms on mortality and recurrent events after myocardial infarction. , 2006, Atherosclerosis.

[22]  E. Souied,et al.  Y402H complement factor H polymorphism associated with exudative age-related macular degeneration in the French population. , 2005, Molecular vision.

[23]  Jian Ge,et al.  CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD , 2005, PLoS medicine.

[24]  Jurg Ott,et al.  Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration. , 2005, American journal of human genetics.

[25]  R. T. Smith,et al.  A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[26]  J. Ott,et al.  Complement Factor H Polymorphism in Age-Related Macular Degeneration , 2005, Science.

[27]  Julian C. Knight,et al.  Regulatory polymorphisms underlying complex disease traits , 2005, Journal of Molecular Medicine.

[28]  M. Sillanpää,et al.  Replication in genetic studies of complex traits , 2004, Annals of human genetics.

[29]  P. Thomas,et al.  Coding single-nucleotide polymorphisms associated with complex vs. Mendelian disease: evolutionary evidence for differences in molecular effects. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Chiara Sabatti,et al.  The use of pedigree, sib-pair and association studies of common diseases for genetic mapping and epidemiology , 2004, Nature Genetics.

[31]  D. Berry.  Bayesian Statistics and the Efficiency and Ethics of Clinical Trials , 2004 .

[32]  D. Allison,et al.  Nonreplication in genetic association studies of obesity and diabetes research. , 2003, The Journal of nutrition.

[33]  M. Olivier.  A haplotype map of the human genome. , 2003, Nature.

[34]  D. Botstein,et al.  Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease , 2003, Nature Genetics.

[35]  E. Lander,et al.  Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease , 2003, Nature Genetics.

[36]  Hiroshi Sato,et al.  Functional SNPs in the lymphotoxin-α gene that are associated with susceptibility to myocardial infarction , 2002, Nature Genetics.

[37]  J. Hirschhorn,et al.  A comprehensive review of genetic association studies , 2002, Genetics in Medicine.

[38]  J Blangero,et al.  Large upward bias in estimation of locus-specific effects from genomewide scans. , 2001, American journal of human genetics.

[39]  J. Ioannidis,et al.  Replication validity of genetic association studies , 2001, Nature Genetics.

[40]  L. Cardon,et al.  Association study designs for complex diseases , 2001, Nature Reviews Genetics.

[41]  N. Risch.  Searching for genetic determinants in the new millennium , 2000, Nature.

[42]  E. Lander,et al.  Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results , 1995, Nature Genetics.

[43]  W. Ewens,et al.  Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). , 1993, American journal of human genetics.

[44]  L. Shulman,et al.  Genome-wide association study identifies novel breast cancer susceptibility loci , 2008 .

[45]  山田 晶.  Lack of association of polymorphisms of the lymphotoxin α gene with myocardial infarction in Japanese , 2007 .

[46]  The International HapMap Consortium.  A haplotype map of the human genome , 2005 .

[47]  Elizabeth M. Smigielski,et al.  dbSNP: the NCBI database of genetic variation , 2001, Nucleic Acids Res..

[48]  G. Abecasis,et al.  Supporting Online Material Materials and Methods Figs. S1 to S8 Tables S1 to S10 References a Genome-wide Association Study of Type 2 Diabetes in Finns Detects Multiple Susceptibility Variants , 2022 .

[49]  M. Jarvelin,et al.  Edinburgh Research Explorer A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity , 2022 .