title: Application of a new method for GWAS in a related case/control sample with known pedigree structure: identification of new loci for nephrolithiasis.
abstract: In contrast to large GWA studies based on thousands of individuals and large meta-analyses combining GWAS results, we analyzed a small case/control sample for uric acid nephrolithiasis. Our cohort of closely related individuals is derived from a small, genetically isolated village in Sardinia, with well-characterized genealogical data linking the extant population up to the 16(th) century. It is expected that the number of risk alleles involved in complex disorders is smaller in isolated founder populations than in more diverse populations, and the power to detect association with complex traits may be increased when related, homogeneous affected individuals are selected, as they are more likely to be enriched with and share specific risk variants than are unrelated, affected individuals from the general population. When related individuals are included in an association study, correlations among relatives must be accurately taken into account to ensure validity of the results. A recently proposed association method uses an empirical genotypic covariance matrix estimated from genome-screen data to allow for additional population structure and cryptic relatedness that may not be captured by the genealogical data. We apply the method to our data, and we also investigate the properties of the method, as well as other association methods, in our highly inbred population, as previous applications were to outbred samples. The more promising regions identified in our initial study in the genetic isolate were then further investigated in an independent sample collected from the Italian population. Among the loci that showed association in this study, we observed evidence of a possible involvement of the region encompassing the gene LRRC16A, already associated to serum uric acid levels in a large meta-analysis of 14 GWAS, suggesting that this locus might lead a pathway for uric acid metabolism that may be involved in gout as well as in nephrolithiasis.
authors.affiliation: Istituto di Genetica delle Popolazioni-CNR, Sassari, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Tore
authors.forename: Stefania
authors.initials: S
authors.lastname: Casula
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Casu
authors.forename: Maria Pina
authors.initials: MP
authors.lastname: Concas
authors.forename: Paola
authors.initials: P
authors.lastname: Pistidda
authors.forename: Ivana
authors.initials: I
authors.lastname: Persico
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sassu
authors.forename: Giovanni Battista
authors.initials: GB
authors.lastname: Maestrale
authors.forename: Caterina
authors.initials: C
authors.lastname: Mele
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Caruso
authors.forename: Bibiana
authors.initials: B
authors.lastname: Bonerba
authors.forename: Paolo
authors.initials: P
authors.lastname: Usai
authors.forename: Ivo
authors.initials: I
authors.lastname: Deiana
authors.forename: Timothy
authors.initials: T
authors.lastname: Thornton
authors.forename: Mario
authors.initials: M
authors.lastname: Pirastu
authors.forename: Paola
authors.initials: P
authors.lastname: Forabosco
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D003627:Data Interpretation, Statistical; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D006073:Gout / Q000235:genetics; D006801:Humans; D007558:Italy; D008840:Microfilament Proteins; D053040:Nephrolithiasis / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D014527:Uric Acid / Q000097:blood / Q000378:metabolism*
chemical_list: C547525:CARMIL1 protein, human; D002352:Carrier Proteins; D008840:Microfilament Proteins; D014527:Uric Acid