ADAMTSL3 as a candidate gene for schizophrenia: gene sequencing and ultra-high density association analysis by imputation.
We previously reported an association with a putative functional variant in the ADAMTSL3 gene, just below genome-wide significance in a genome-wide association study of schizophrenia. As variants impacting the function of ADAMTSL3 (a disintegrin-like and metalloprotease domain with thrombospondin type I motifs-like-3) could illuminate a novel disease mechanism and a potentially specific target, we have used complementary approaches to further evaluate the association. We imputed genotypes and performed high density association analysis using data from the HapMap and 1000 genomes projects. To review all variants that could potentially cause the association, and to identify additional possible pathogenic rare variants, we sequenced ADAMTSL3 in 92 schizophrenics. A total of 71 ADAMTSL3 variants were identified by sequencing, many were also seen in the 1000 genomes data, but 26 were novel. None of the variants identified by re-sequencing was in strong linkage disequilibrium (LD) with the associated markers. Imputation analysis refined association between ADAMTSL3 and schizophrenia, and highlighted additional common variants with similar levels of association. We evaluated the functional consequences of all variants identified by sequencing, or showing direct or imputed association. The strongest evidence for function remained with the originally associated variant, rs950169, suggesting that this variant may be causal of the association. Rare variants were also identified with possible functional impact. Our study confirms ADAMTSL3 as a candidate for further investigation in schizophrenia, using the variants identified here. The utility of imputation analysis is demonstrated, and we recommend wider use of this method to re-evaluate the existing canon of suggestive schizophrenia associations.
Molecular Discovery Research, GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park (North), Third Avenue, Harlow, CM19 5AW, UK. David.J.Dow@gsk.com
David J
DJ
Dow
Julie
J
Huxley-Jones
Jamie M
JM
Hall
Clyde
C
Francks
Peter R
PR
Maycox
James N C
JN
Kew
Israel S
IS
Gloger
Nalini A L
NA
Mehta
Fiona M
FM
Kelly
Pierandrea
P
Muglia
Gerome
G
Breen
Sarah
S
Jugurnauth
Inti
I
Pederoso
David
D
St Clair
Dan
D
Rujescu
Michael R
MR
Barnes
D000071096:ADAMTS Proteins; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics*
C491337:ADAMTSL3 protein, human; D016326:Extracellular Matrix Proteins; D000071096:ADAMTS Proteins