BACKGROUND: Clubfoot is a common congenital birth defect with complex inheritance patterns. Currently, the genetic and morphological basis of clubfoot is poorly understood. To identify genetic risk factors associated with clubfoot, we performed a genome-wide association study of common genetic variants. METHODS: The DNA of 396 isolated clubfoot patients and 1000 controls of European descent was genotyped for >600 000 single nucleotide polymorphisms (SNP) using the Affymetrix 6.0 array. Replication was performed with an independent cohort of 370 isolated clubfoot cases and 363 controls of European descent. RESULTS: Strongest evidence for an association of clubfoot was found with an intergenic SNP on chromosome 12q24.31 between NCOR2 and ZNF664 (rs7969148, OR=0.58, p=1.25×10⁻⁵) that was significant on replication (combined OR=0.63, p=1.90×10⁻⁷). Additional suggestive SNPs were identified near FOXN3, SORCS1 and MMP7/TMEM123 that also confirmed on replication. CONCLUSIONS: Our study suggests a potential role for common genetic variation in several genes that have not previously been implicated in clubfoot pathogenesis.
BACKGROUND: Clubfoot is a common congenital birth defect with complex inheritance patterns. Currently, the genetic and morphological basis of clubfoot is poorly understood. To identify genetic risk factors associated with clubfoot, we performed a genome-wide association study of common genetic variants. METHODS: The DNA of 396 isolated clubfoot patients and 1000 controls of European descent was genotyped for >600 000 single nucleotide polymorphisms (SNP) using the Affymetrix 6.0 array. Replication was performed with an independent cohort of 370 isolated clubfoot cases and 363 controls of European descent. RESULTS: Strongest evidence for an association of clubfoot was found with an intergenic SNP on chromosome 12q24.31 between NCOR2 and ZNF664 (rs7969148, OR=0.58, p=1.25×10⁻⁵) that was significant on replication (combined OR=0.63, p=1.90×10⁻⁷). Additional suggestive SNPs were identified near FOXN3, SORCS1 and MMP7/TMEM123 that also confirmed on replication. CONCLUSIONS: Our study suggests a potential role for common genetic variation in several genes that have not previously been implicated in clubfoot pathogenesis.
Entities:
Keywords:
clubfoot; genome wide association study; transcription factor
Authors: Anas M Khanshour; Yared H Kidane; Julia Kozlitina; Reuel Cornelia; Alexandra Rafipay; Vanessa De Mello; Mitchell Weston; Nandina Paria; Aysha Khalid; Jacqueline T Hecht; Matthew B Dobbs; B Stephens Richards; Neil Vargesson; F Kent Hamra; Megan Wilson; Carol Wise; Christina A Gurnett; Jonathan J Rios Journal: Hum Mol Genet Date: 2021-01-21 Impact factor: 6.150
Authors: Lord J J Gowans; Noura Al Dhaheri; Mary Li; Tamara Busch; Solomon Obiri-Yeboah; Alexander A Oti; Daniel K Sabbah; Fareed K N Arthur; Waheed O Awotoye; Azeez A Alade; Peter Twumasi; Pius Agbenorku; Gyikua Plange-Rhule; Thirona Naicker; Peter Donkor; Jeffrey C Murray; Nara L M Sobreira; Azeez Butali Journal: Mol Genet Genomic Med Date: 2021-03-14 Impact factor: 2.183