Hypothesis-Driven Candidate Gene Association Studies: Practical Design and Analytical Considerations

Jorgensen, Timothy J.; Ruczinski, Ingo; Kessing, Bailey; Smith, Michael W.; Shugart, Yin Yao; Alberg, Anthony J.

doi:10.1093/aje/kwp242

Cited by 79 publications

(63 citation statements)

References 54 publications

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“…In particular, most recent genetic association studies have been covered by single nucleotide polymorphism (SNP) analyses using the genome-wide association study (GWAS) design [37,57], but replication has proved somewhat difficult due to the need for large samples of patients and controls, the high cost entailed and the fact that lack of a previous hypothesis hampers explanation of some of the observed results. New approaches, such as the candidate gene association study (CGAS) design [36], based on testing an a priori hypothesis and focused on a specific genome region, is a good method for applying to rare diseases in cases where recruiting a large cohort of patients poses problems; and, in addition, it may afford better, direct interpretation of results. Selecting the appropriate pathway from among all those available, i.e., the one that best relates genes from the various known regions and disease mechanisms, is crucial for the success of this type of studies.…”

Section: From Descriptive To Epigenetic Epidemiologymentioning

confidence: 99%

Rare Diseases Epidemiology Research

Paz

Villaverde-Hueso

Alonso-Ferreira

et al. 2010

Rare Diseases Epidemiology

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Rare Diseases Epidemiology is a novel action field still largely unexplored. However, Rare Diseases is a topic of growing interest at world level. The aims of this chapter are to revise useful epidemiological tools and define areas where epidemiology can help improve the rare disease knowledge, and facilitate policy decisions taking into account the real burden of rare diseases in society. This chapter also seeks to describe: the problems of coding and classification of diseases, measuring disease frequency, the study designs and association studies, the causality, the evolution from descriptive to epigenetic epidemiology and the natural history of disease. One of the major challenges facing analytical epidemiology and clinical epidemiological research into rare diseases is that genes can be involved in both aetiology and prognosis. Despite the many similarities between genetic association studies and classic observational epidemiological studies, the former pose several specific limitations, including an unprecedented volume of new data and the likelihood of very small individual effects, as well other limitations. Selecting the appropriate pathway from among all those available, i.e. the one that best relates genes from the various known regions and disease mechanisms, is crucial for the success of this type of studies.

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Section: From Descriptive To Epigenetic Epidemiologymentioning

confidence: 99%

Rare Diseases Epidemiology Research

Paz

Villaverde-Hueso

Alonso-Ferreira

et al. 2010

Rare Diseases Epidemiology

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“…Overall, the studies of GST enzyme polymorphisms and OS risk have been inconsistent, further well-designed studies (Jorgensen et al, 2009) in additional populations are needed to clarify these associations.…”

Section: Candidate Snps Associated With Os: Detoxification Genesmentioning

confidence: 99%

Osteosarcoma: Genetics of Inherited Susceptibility

Mirabello

2013

Encyclopedia of Life Sciences

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Osteosarcoma (OS) is the most common primary malignant bone tumour that typically occurs in adolescents and young adults. OS incidence has been related to growth and height, age, gender, ethnicity, certain inherited cancer predisposition syndromes, abnormal bone growth and therapeutic radiation. However, most cases are sporadic (not associated with an inherited syndrome) and no specific genetic or environmental predisposing factor has been identified. A common genetic susceptibility locus has not been found. Germline genetics refers to deoxyribonucleic acid (DNA) sequence changes that are inherited and present in all cells of the body versus an acquired or somatic mutation. Germline candidate gene association studies have identified several common single nucleotide polymorphisms (SNPs) associated with risk of OS, including genes important in growth, cell cycle checkpoint control and tumour immunity. Recently, the first genome‐wide association study was conducted and further expands our understanding of the germline genetics of OS. Key Concepts: Epidemiologic studies have provided many important clues about the aetiology of OS, including an association with bone growth, which have directed much of the search for candidate genes associated with risk of OS. OS is associated with several rare inherited cancer predisposition syndromes (Li–Fraumeni syndrome, hereditary bilateral retinoblastoma, Bloom, Werner, Rothmund Thomson syndromes, and Diamond–Blackfan anemia) that are caused by highly penetrant germline mutations. These syndromes are not a common cause of OS. Candidate gene association studies have suggested several polymorphisms associated with risk of OS; SNP associations in the following candidate genes have been replicated in two or more studies: IGF2R , FGFR3 , MDM2 , TGFBR1 and CTLA‐4 . An agnostic genome‐wide association study has found two novel loci associated with risk of OS: GRM4 gene and the 2p25.2 chromosomal region. Studies are needed to expand these genetic association findings to more ethnic groups and in larger samples sizes to determine if these are stable associations.

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“…This approach is based on a hypothesis-driven pathway in contrast to genome-wide association studies (GWAS), generally considered as more ‘agnostic’ in the field of genetic studies [38]. …”

Section: Genetic Studiesmentioning

confidence: 99%