Identification of a novel susceptibility locus for nonsyndromic cleft lip and palate at chromosome 15q13. K. U. Ludwig1,2, A. C. Boehmer1,2, H. Peters3, D. Graf4, P. Gültepe1,2, P. A. Mossey5, R. P. Steegers-Theunissen6,7, M. Rubini8, M. M. Nöthen1,2, M. Knapp9, E. Mangold1 1) Institute of Human Genetics, University of Bonn, Bonn, Germany; 2) Department of Genomics, University of Bonn, Bonn, Germany; 3) Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK; 4) School of Dentistry, University of Alberta, Edmonton, Canada; 5) Orthodontic Unit, Dental Hospital & School, University of Dundee, Dundee, UK; 6) Erasmus Medical Center, University Medical Center, Rotterdam, The Netherlands; 7) Radboud University Medical Center, Nijmegen, The Netherlands; 8) Department of Biomedical and Specialty Surgical Sciences, Medical Genetics Unit, University of Ferrara, Ferrara, Italy; 9) Institute of Medical Biometry Informatics and Epidemiology, University of Bonn, Bonn, Germany.
Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is one of the most common congenital malformations worldwide. The etiology of nsCL/P is multifactorial. There is a considerable phenotypic variability associated with the trait, the main subgroups being nonsyndromic cleft lip only (nsCLO) and nonsyndromic cleft lip with cleft palate (nsCLP). Data from both epidemiology and embryology suggest that genetic factors might contribute to this variability. In the last years, genome-wide studies have identified 15 nsCL/P susceptibility loci explaining about 20% of nsCL/P heritability. In our recent meta-analysis (Ludwig et al. 2012, Nature Genetics) we observed a number of variants in the range of 10-05>P>5×10-08, and some of these might be true genetic risk loci. As lack of power could explain why true risk loci fail to reach genome-wide significance, we investigated some of the variants in an independent European trio cohort (n=793). One variant, rs1258763 on chr. 15q13 (P=1.81×10-06), was replicated in that sample (P=0.038), resulting in P=4.83×10-07 in the combined analysis. Integration of subgroup-information on nsCLO or nsCLP further decreased that P-value, now reaching genome-wide significance in the nsCLP group (P=1.04×10-08, odds ratio = 1.38 per allele). The top variant rs1258763 has previously been shown to be associated with an increased nose width (Boehringer et al. 2011, EJHG, Liu et al. 2012, PloS Genetics), suggesting that it also contributes to human facial variation. The associated region maps intergenically, between the Gremlin-1 (GREM1) and Formin-1 (FMN1) genes. GREM1 is a known antagonist of the BMP4 pathway which is relevant to craniofacial genesis. Sequencing the GREM1coding region plus UTR in about 400 individuals revealed a significant overrepresentation of rare variants within patients (P=0.02). Based on analyses of the murine Grem1 expression pattern during embryonic craniofacial development, we further subdivided our nsCLP patient cohort and identified a strong increase in the odds ratio, which reached 3.76 per allele in a group of patients with a specific, and clinically relevant subtype of nsCLP. Notably, in four of six multiplex-families with rare mutations in GREM1, the rare allele also co-segregated with this particular clinical subtype. Our results demonstrate that the combination of increasing sample sizes and analysing sub-phenotypes might help to identify further risk loci for genetically complex traits.
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