On the replication of genetic associations: timing can be everything!
The failure of researchers to replicate genetic-association findings is most commonly attributed to insufficient statistical power, population stratification, or various forms of between-study heterogeneity or environmental influences.(1) Here, we illustrate another potential cause for nonreplications that has so far not received much attention in the literature. We illustrate that the strength of a genetic effect can vary by age, causing "age-varying associations." If not taken into account during the design and the analysis of a study, age-varying genetic associations can cause nonreplication. By using the 100K SNP scan of the Framingham Heart Study, we identified an age-varying association between a SNP in ROBO1 and obesity and hypothesized an age-gene interaction. This finding was followed up in eight independent samples comprising 13,584 individuals. The association was replicated in five of the eight studies, showing an age-dependent relationship (one-sided combined p = 3.92 x 10(-9), combined p value from pediatric cohorts = 2.21 x 10(-8), combined p value from adult cohorts = 0.00422). Furthermore, this study illustrates that it is difficult for cross-sectional study designs to detect age-varying associations. If the specifics of age- or time-varying genetic effects are not considered in the selection of both the follow-up samples and in the statistical analysis, important genetic associations may be missed.
Lasky-Su
Jessica
J
SUNY Upstate Medical University, Syracuse, NY 13210, USA. jessica.a.su@gmail.com
Lyon
Helen N
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Emilsson
Valur
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Heid
Iris M
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Molony
Cliona
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Raby
Benjamin A
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Lazarus
Ross
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Klanderman
Barbara
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Soto-Quiros
Manuel E
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Avila
Lydiana
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Silverman
Edwin K
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Thorleifsson
Gudmar
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Thorsteinsdottir
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Kronenberg
Florian
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Vollmert
Caren
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Illig
Thomas
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Fox
Caroline S
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Levy
Daniel
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Laird
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Ding
Xiao
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McQueen
Matt B
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Butler
Johannah
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Ardlie
Kristin
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Papoutsakis
Constantina
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Dedoussis
George
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O'Donnell
Christopher J
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Wichmann
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Celedón
Juan C
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Schadt
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Hirschhorn
Joel
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Weiss
Scott T
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Stefansson
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Lange
Christoph
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D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D015992:Body Mass Index; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D005787:Gene Frequency; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009765:Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011971:Receptors, Immunologic / Q000235:genetics*; D000097905:Roundabout Proteins
D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D000097905:Roundabout Proteins