title: On the replication of genetic associations: timing can be everything!
abstract: 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.
authors.affiliation: SUNY Upstate Medical University, Syracuse, NY 13210, USA. jessica.a.su@gmail.com
authors.forename: Jessica
authors.initials: J
authors.lastname: Lasky-Su
authors.forename: Helen N
authors.initials: HN
authors.lastname: Lyon
authors.forename: Valur
authors.initials: V
authors.lastname: Emilsson
authors.forename: Iris M
authors.initials: IM
authors.lastname: Heid
authors.forename: Cliona
authors.initials: C
authors.lastname: Molony
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Raby
authors.forename: Ross
authors.initials: R
authors.lastname: Lazarus
authors.forename: Barbara
authors.initials: B
authors.lastname: Klanderman
authors.forename: Manuel E
authors.initials: ME
authors.lastname: Soto-Quiros
authors.forename: Lydiana
authors.initials: L
authors.lastname: Avila
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.forename: Florian
authors.initials: F
authors.lastname: Kronenberg
authors.forename: Caren
authors.initials: C
authors.lastname: Vollmert
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
authors.forename: Daniel
authors.initials: D
authors.lastname: Levy
authors.forename: Nan
authors.initials: N
authors.lastname: Laird
authors.forename: Xiao
authors.initials: X
authors.lastname: Ding
authors.forename: Matt B
authors.initials: MB
authors.lastname: McQueen
authors.forename: Johannah
authors.initials: J
authors.lastname: Butler
authors.forename: Kristin
authors.initials: K
authors.lastname: Ardlie
authors.forename: Constantina
authors.initials: C
authors.lastname: Papoutsakis
authors.forename: George
authors.initials: G
authors.lastname: Dedoussis
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Juan C
authors.initials: JC
authors.lastname: Celedón
authors.forename: Eric
authors.initials: E
authors.lastname: Schadt
authors.forename: Joel
authors.initials: J
authors.lastname: Hirschhorn
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.forename: Christoph
authors.initials: C
authors.lastname: Lange
mesh_terms: 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
chemical_list: D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D000097905:Roundabout Proteins