REPORT Common Variants in the Trichohyalin Gene Are Associated with Straight Hair in Europeans Sarah E. Medland, 1, * Dale R. Nyholt, 1 Jodie N. Painter, 1 Brian P. McEvoy, 1 Allan F. McRae, 1 Gu Zhu, 1 Scott D. Gordon, 1 Manuel A.R. Ferreira, 1 Margaret J. Wright, 1 Anjali K. Henders, 1 Megan J. Campbell, 1 David L. Duffy, 1 Narelle K. Hansell, 1 Stuart Macgregor, 1 Wendy S. Slutske, 2 Andrew C. Heath, 3 Grant W. Montgomery, 1 and Nicholas G. Martin 1 Hair morphology is highly differentiated between populations and among people of European ancestry. Whereas hair morphology in East Asian populations has been studied extensively, relatively little is known about the genetics of this trait in Europeans. We performed a genome-wide association scan for hair morphology (straight, wavy, curly) in three Australian samples of European descent. All three samples showed evidence of association implicating the Trichohyalin gene (TCHH), which is expressed in the developing inner root sheath of the hair follicle, and explaining ~6% of variance (p ¼ 1.5 3 10 31 ). These variants are at their highest frequency in Northern Europeans, paralleling the distribution of the straight-hair EDAR variant in Asian populations. Hair morphology is one of the more conspicuous features of human variation and is particularly diverse among people of European ancestry, for which around 45% of individuals have straight hair, 40% have wavy hair, and 15% have curly hair. 1 The degree of curliness is correlated with the distribution of hair keratins and cell type within the hair fiber, with the number of mesocortical cells decreasing as the curl intensifies. 2 Recent studies have identified Asian-specific alleles of the EDAR and FGFR2 genes that are associated with thick, straight hair, suggest- ing that these variants arose after the divergence of Asians and Europeans. 3,4 However, the genetic variants influ- encing hair curliness in Europeans (which has been shown to be highly heritable 5 ) are unknown. We conducted genome-wide association analyses in three Australian family samples: one sample of adolescent twins and their siblings (1649 individuals from 837 fami- lies) and two samples of adult twin pairs (S1, 1945 individuals from 1210 families; S2, 1251 individuals from 845 families) ascertained from the general population (Table 1). 5 In the adolescent sample, hair curliness was rated on a three-point scale (Straight, Wavy, or Curly). In the adult samples, participants reported whether their hair was Straight or Curly (S1) or Straight, Wavy, or Curly (S2). To account for the differences in phenotype collec- tion and age across the samples, each sample was analyzed independently and meta-analysis was used for combining the three sets of results. These studies were performed with the approval of the appropriate ethics committees and the informed consent of all participants. The genotypic data used in the current study derives from a larger genotyping project involving seven waves of genotyping that drew participants from our 1988 and 1990 adult health and lifestyle studies 6 and adolescent melanoma risk factors study. 7,8 The genotypic data from each project are described in Table 2. Standard quality- control filters were applied to the genotyping from each project, restricting the imputation to samples and SNPs with high data quality (Table 2). Individuals were screened for non-European ancestry, resulting in a sample of 16,140 genotyped individuals (Figure S2, available online). So that bias was not introduced to the imputed data, a set of SNPs common to the seven subsamples was used for imputation (n ¼ 274,604). Imputation was undertaken with the use of the phased data from the HapMap samples of European ancestry (CEU; build 36, release 22) and MACH. 9 So that we could take full advantage of the information available in the ordinal scale, the data were analyzed via a multifactorial threshold model that describes discrete traits as reflecting an underlying normal distribution of liability (or predisposition). Liability, which represents the sum of all the multifactorial effects, is assumed to reflect the combined additive effects of a large number of genes and environmental factors, each of small effect, and is characterized by phenotypic discontinuities that occur when the liability reaches a given threshold. 10 A total test of association was used, in which the dosage (MACH mldose) data for each SNP in turn were included within the threshold model, resulting in an additive test of association. In addition, fixed effects of sex and age (both linear and quadratic effects) and age-by-sex interactions were included with the threshold models in all data anal- yses, such that the trait value for individual j from family i was parameterized as: x ij ¼ b dose þ b age þ b age 2 þ b sex þ b sex-age þ m. The relatedness between the participants was explicitly modeled, accounting for the sex of relative pairs, and the phenotypic variances were constrained to unity. The association test statistic was computed by comparing the fit (minus twice log-likelihood) of the full model, which included the effect of the given SNP, to that of 1 Queensland Institute of Medical Research, Brisbane 4029, Australia; 2 University of Missouri, Columbia, MO 65211, USA; 3 Washington University School of Medicine, St Louis, MO 63110, USA *Correspondence: sarahme@qimr.edu.au DOI 10.1016/j.ajhg.2009.10.009. ª2009 by The American Society of Human Genetics. All rights reserved. 750 The American Journal of Human Genetics 85, 750–755, November 13, 2009