Genome-wide analysis of copy number variants and normal facial variation in a large cohort of Bantu Africans
Megan Null,
Feyza Yilmaz,
David Astling,
Hung-Chun Yu,
Joanne B. Cole,
Benedikt Hallgrímsson,
Stephanie A. Santorico,
Richard A. Spritz,
Tamim H. Shaikh,
Audrey E. Hendricks
Affiliations
Megan Null
Mathematical and Statistical Sciences, University of Colorado Denver, Denver, CO, USA; Department of Mathematics and Physical Sciences, The College of Idaho, Caldwell, ID 83605, USA
Feyza Yilmaz
Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Integrative Biology, University of Colorado Denver, Denver, CO 80204, USA
David Astling
Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Hung-Chun Yu
Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Joanne B. Cole
Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Human Medical Genetics and Genomics Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Benedikt Hallgrímsson
Department of Cell Biology & Anatomy, Alberta Children Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 1N4, Canada
Stephanie A. Santorico
Mathematical and Statistical Sciences, University of Colorado Denver, Denver, CO, USA; Human Medical Genetics and Genomics Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Biostatistics and Informatics, Colorado School of Public Health, Aurora, CO 80045, USA
Richard A. Spritz
Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Human Medical Genetics and Genomics Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Tamim H. Shaikh
Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Human Medical Genetics and Genomics Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Corresponding author
Audrey E. Hendricks
Mathematical and Statistical Sciences, University of Colorado Denver, Denver, CO, USA; Human Medical Genetics and Genomics Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA; Biostatistics and Informatics, Colorado School of Public Health, Aurora, CO 80045, USA; Corresponding author
Similarity in facial characteristics between relatives suggests a strong genetic component underlies facial variation. While there have been numerous studies of the genetics of facial abnormalities and, more recently, single nucleotide polymorphism (SNP) genome-wide association studies (GWASs) of normal facial variation, little is known about the role of genetic structural variation in determining facial shape. In a sample of Bantu African children, we found that only 9% of common copy number variants (CNVs) and 10-kb CNV analysis windows are well tagged by SNPs (r2 ≥ 0.8), indicating that associations with our internally called CNVs were not captured by previous SNP-based GWASs. Here, we present a GWAS and gene set analysis of the relationship between normal facial variation and CNVs in a sample of Bantu African children. We report the top five regions, which had p values ≤ 9.35 × 10−6 and find nominal evidence of independent CNV association (p < 0.05) in three regions previously identified in SNP-based GWASs. The CNV region with strongest association (p = 1.16 × 10−6, 55 losses and seven gains) contains NFATC1, which has been linked to facial morphogenesis and Cherubism, a syndrome involving abnormal lower facial development. Genomic loss in the region is associated with smaller average lower facial depth. Importantly, new loci identified here were not identified in a SNP-based GWAS, suggesting that CNVs are likely involved in determining facial shape variation. Given the plethora of SNP-based GWASs, calling CNVs from existing data may be a relatively inexpensive way to aid in the study of complex traits.
