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1.
Ann Rheum Dis ; 72(3): 427-36, 2013 Mar.
Article in English | MEDLINE | ID: mdl-22956598

ABSTRACT

BACKGROUND AND OBJECTIVES: Chronic widespread pain (CWP) is a common disorder affecting ∼10% of the general population and has an estimated heritability of 48-52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP. METHODS: We conducted a GWAS meta-analysis in 1308 female CWP cases and 5791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1480 CWP cases and 7989 controls. Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain. RESULTS: The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of chaperonin-containing-TCP1-complex-5 gene (CCT5) and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (minor allele frequency=43%; OR=1.30, 95% CI 1.19 to 1.42, p=1.2×10(-8)). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7×10(-7)) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95% CI 1.14 to 1.32, p=3.4×10(-8), I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (p>7.7×10(-4)). CONCLUSIONS: We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.


Subject(s)
Chromosomes, Human, Pair 5/genetics , Chronic Pain/genetics , Genome-Wide Association Study , Animals , Disease Models, Animal , Female , Genetic Predisposition to Disease , Genotype , Humans , Mice , Polymorphism, Single Nucleotide
2.
Nat Genet ; 44(3): 260-8, 2012 Jan 22.
Article in English | MEDLINE | ID: mdl-22267201

ABSTRACT

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.


Subject(s)
DNA Repair/genetics , Genetic Loci/genetics , Immunity/genetics , Menopause/genetics , Polymorphism, Single Nucleotide/genetics , Age Factors , DNA Helicases/genetics , DNA Polymerase gamma , DNA Primase/genetics , DNA Repair Enzymes/genetics , DNA-Directed DNA Polymerase/genetics , Exodeoxyribonucleases/genetics , Female , Genome-Wide Association Study , Humans , Menopause/physiology , Proteins/genetics , White People/genetics
3.
Nat Genet ; 42(12): 1077-85, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21102462

ABSTRACT

To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻6°) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻8) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻6). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.


Subject(s)
Aging/physiology , Genetic Loci/genetics , Genome-Wide Association Study , Menarche/genetics , Adolescent , Body Height/genetics , Body Size/genetics , Child , DNA Copy Number Variations/genetics , Female , Genetic Predisposition to Disease , Humans , Inheritance Patterns/genetics , Obesity/genetics , Polymorphism, Single Nucleotide/genetics , Quantitative Trait Loci/genetics , Reproducibility of Results , Time Factors
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