title: Genetic determination of human facial morphology: links between cleft-lips and normal variation.
abstract: Recent genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with non-syndromic cleft lip with or without cleft palate (NSCL/P), and other previous studies showed distinctly differing facial distance measurements when comparing unaffected relatives of NSCL/P patients with normal controls. Here, we test the hypothesis that genetic loci involved in NSCL/P also influence normal variation in facial morphology. We tested 11 SNPs from 10 genomic regions previously showing replicated evidence of association with NSCL/P for association with normal variation of nose width and bizygomatic distance in two cohorts from Germany (N=529) and the Netherlands (N=2497). The two most significant associations found were between nose width and SNP rs1258763 near the GREM1 gene in the German cohort (P=6 × 10(-4)), and between bizygomatic distance and SNP rs987525 at 8q24.21 near the CCDC26 gene (P=0.017) in the Dutch sample. A genetic prediction model explained 2% of phenotype variation in nose width in the German and 0.5% of bizygomatic distance variation in the Dutch cohort. Although preliminary, our data provide a first link between genetic loci involved in a pathological facial trait such as NSCL/P and variation of normal facial morphology. Moreover, we present a first approach for understanding the genetic basis of human facial appearance, a highly intriguing trait with implications on clinical practice, clinical genetics, forensic intelligence, social interactions and personal identity.
authors.affiliation: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands. correspondence@s-boehringer.org
authors.forename: Stefan
authors.initials: S
authors.lastname: Boehringer
authors.forename: Fedde
authors.initials: F
authors.lastname: van der Lijn
authors.forename: Fan
authors.initials: F
authors.lastname: Liu
authors.forename: Manuel
authors.initials: M
authors.lastname: Günther
authors.forename: Stella
authors.initials: S
authors.lastname: Sinigerova
authors.forename: Stefanie
authors.initials: S
authors.lastname: Nowak
authors.forename: Kerstin U
authors.initials: KU
authors.lastname: Ludwig
authors.forename: Ruth
authors.initials: R
authors.lastname: Herberz
authors.forename: Stefan
authors.initials: S
authors.lastname: Klein
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Wiro J
authors.initials: WJ
authors.lastname: Niessen
authors.forename: Monique M B
authors.initials: MM
authors.lastname: Breteler
authors.forename: Aad
authors.initials: A
authors.lastname: van der Lugt
authors.forename: Rolf P
authors.initials: RP
authors.lastname: Würtz
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: Bernhard
authors.initials: B
authors.lastname: Horsthemke
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mangold
authors.forename: Manfred
authors.initials: M
authors.lastname: Kayser
mesh_terms: D000293:Adolescent; D000328:Adult; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008445:Maxillofacial Development / Q000235:genetics*; D008957:Models, Genetic; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors; D044465:White People / Q000235:genetics; D055815:Young Adult