EDA2R Is Associated with Androgenetic Alopecia

Prodi, Dionigio Antonio; Pirastu, Nicola; Maninchedda, Giuseppe; Sassu, Alessandro; Picciau, Andrea; Palmas, Maria Antonietta; Mossa, Alessandra; Persico, Ivana; Adamo, Mauro F. A.; Angius, Andrea; Pirastu, Mario

doi:10.1038/jid.2008.60

Cited by 86 publications

(78 citation statements)

References 20 publications

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“…A common synonymous coding variant rs6152 G4A (StuI restriction site) in the exon 1 of the AR gene has been associated with MPB in previous studies. 11,12 For example, Ellis et al 11 found that in an Australian cohort the G allele was present in 98.1% of young bald men, 92.3% of older bald men, and only 76.6% of non-bald men. The variant rs6152 is available in RS and was also highly significantly associated with MPB (P = 5.6 × 10 − 8 ) but much less so than the top-associated X-chromosomal SNP rs1511061 (P = 2.6 × 10 − 11 in RS), and it became nonsignificant (P40.05) when conditioning on the genotypes of rs1511061.…”

Section: Discussionmentioning

confidence: 99%

“…10 A locus on chromosome Xq12 harboring the androgen receptor gene (AR) and its neighboring ectodysplasin A2 receptor gene (EDA2R) is known as the major locus for MPB. 11,12 In addition, two genetic loci on chromosome 20p11 (PAX1/FOXA2) and 7p21.1 (HDAC9) were identified to be involved in MPB. [13][14][15] A meta-analysis of seven GWASs for early-onset MPB involving~13 000 individuals of European origin conducted by the International MAAN Consortium 16 replicated these loci and highlighted five additional loci showing genome-wide significant association with MPB; these included 1p36.22, 2q37.3, 7q11.22, 17q21.31, and 18q12.3.…”

Section: Introductionmentioning

confidence: 99%

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Prediction of male-pattern baldness from genotypes

et al. 2015

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The global demand for products that effectively prevent the development of male-pattern baldness (MPB) has drastically increased. However, there is currently no established genetic model for the estimation of MPB risk. We conducted a prediction analysis using single-nucleotide polymorphisms (SNPs) identified from previous GWASs of MPB in a total of 2725 German and Dutch males. A logistic regression model considering the genotypes of 25 SNPs from 12 genomic loci demonstrates that early-onset MPB risk is predictable at an accuracy level of 0.74 when 14 SNPs were included in the model, and measured using the area under the receiver-operating characteristic curves (AUC). Considering age as an additional predictor, the model can predict normal MPB status in middle-aged and elderly individuals at a slightly lower accuracy (AUC 0.69-0.71) when 6-11 SNPs were used. A variance partitioning analysis suggests that 55.8% of early-onset MPB genetic liability can be explained by common autosomal SNPs and 23.3% by X-chromosome SNPs. For normal MPB status in elderly individuals, the proportion of explainable variance is lower (42.4% for autosomal and 9.8% for X-chromosome SNPs). The gap between GWAS findings and the variance partitioning results could be explained by a large body of common DNA variants with small effects that will likely be identified in GWAS of increased sample sizes. Although the accuracy obtained here has not reached a clinically desired level, our model was highly informative for up to 19% of Europeans, thus may assist decision making on early MPB intervention actions and in forensic investigations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prediction of male-pattern baldness from genotypes

et al. 2015

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“…For some of the genes analyzed, there is evidence for biological consequences of the amino acid difference investigated here (Figure 1): EDAR rs3827760 influences NF-kB activity (Bryk et al 2008) and hair thickness (Fujimoto et al 2008a,b), including in a mouse model (Mou et al 2008), and thus might have been sexually selected; the alcohol dehydrogenases metabolize alcohol and rs1229984 in ADH1B is associated with protection against alcoholism (H. ; SLC24A5 is one of the major loci contributing to light skin color in Europeans (Lamason et al 2005); ABCC11 rs17822931 determines wet/dry earwax type (Yoshiura et al 2006); and rs1385699 in EDA2R has been associated with male-pattern baldness (Prodi et al 2008). For other genes, more general information is available about possible biological functions of the gene, although not the consequences of the specific amino acid change studied: for example, ALMS1 is implicated in carbohydrate metabolism (Scheinfeldt et al 2009), RNF135 in growth regulation (Douglas et al 2007), and CEACAM1 in a wide range of functions including infection (Kuespert et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Population Differentiation as an Indicator of Recent Positive Selection in Humans: An Empirical Evaluation

et al. 2009

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We have evaluated the extent to which SNPs identified by genomewide surveys as showing unusually high levels of population differentiation in humans have experienced recent positive selection, starting from a set of 32 nonsynonymous SNPs in 27 genes highlighted by the HapMap1 project. These SNPs were genotyped again in the HapMap samples and in the Human Genome Diversity Project-Centre d'Etude du Polymorphisme Humain (HGDP-CEPH) panel of 52 populations representing worldwide diversity; extended haplotype homozygosity was investigated around all of them, and full resequence data were examined for 9 genes (5 from public sources and 4 from new data sets). For 7 of the genes, genotyping errors were responsible for an artifactual signal of high population differentiation and for 2, the population differentiation did not exceed our significance threshold. For the 18 genes with confirmed high population differentiation, 3 showed evidence of positive selection as measured by unusually extended haplotypes within a population, and 7 more did in between-population analyses. The 9 genes with resequence data included 7 with high population differentiation, and 5 showed evidence of positive selection on the haplotype carrying the nonsynonymous SNP from skewed allele frequency spectra; in addition, 2 showed evidence of positive selection on unrelated haplotypes. Thus, in humans, high population differentiation is (apart from technical artifacts) an effective way of enriching for recently selected genes, but is not an infallible pointer to recent positive selection supported by other lines of evidence. I N the last 50,000-100,000 years (KY), humans have expanded from being a rare species confined to parts of Africa and the Levant to their current numbers of .6 billion with a worldwide distribution ( Jobling et al. 2004). Paleontological and archaeological evidence suggests that key aspects of modern human behavior developed $100-50 KYA in Africa (Henshilwood et al. 2002) and behaviorally modern humans then expanded out of Africa $60-40 KYA (Mellars 2006). The physical and biological environments encountered outside Africa would have been very different from those inside and included climatic deterioration reaching a glacial maximum $20 KYA and subsequent amelioration that permitted the development of agricultural and pastoral lifestyles in multiple independent centers after $10 KYA. Neolithic lifestyles would have led to further changes including higher population densities, close contact with animals, and novel foods, in turn leading to new diseases ( Jobling et al. 2004). It is likely that genetic adaptations accompanied many of these events.Adaptation, or positive natural selection, leaves an imprint on the pattern of genetic variation found in a population near the site of selection. This pattern can be identified by comparing the DNA variants in multiple individuals from the same and different populations and searching for signals such as unusually extended haplotypes (extended haplotype homozygosity, EHH) (Voight ...

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“…For ectodysplasin A2 receptor (EDA2R), a nonsynonymous SNP (rs1385699) was genotyped, because rs1385699 was recently reported to be involved in androgenetic alopecia. 10,11 In total, 17 SNPs of the 14 candidate genes listed in Table 1 were genotyped using either the DigiTag2 method 12 or PCR-direct sequencing.…”

Section: Snp Selection and Genotypingmentioning

confidence: 99%

FGFR2 is associated with hair thickness in Asian populations

et al. 2009

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Hair morphology is one of the most differentiated traits among human populations. A previous study has shown that a nonsynonymous single nucleotide polymorphism (SNP) in the EDAR gene, EDAR 1540T/C, is strongly associated with hair thickness in Asian populations. However, the contributions of other genes remain to be elucidated. In this study, 12 SNPs on 10 hair formation-related genes with high differentiation between Asian and other populations were examined to further identify genes associated with hair morphology. A multiple regression analysis adjusted for age, sex, population and the effect of EDAR 1540T/C revealed an SNP in intron 9 of FGFR2, rs4752566, to be significantly associated with hair thickness (cross-sectional area; P-value¼0.0052, small diameter; P-value¼0.029 and large diameter; P-value¼0.0015). In the genomic region containing the FGFR2 gene, rs4752566 was not in strong linkage disequilibrium (LD) with the surrounding SNPs, indicating that the significant association of rs4752566 with the hair thickness is not due to LD with polymorphisms of the other genes. The rs4752566-T allele of FGFR2, associated with thicker hair, was also shown to be associated with higher mRNA level of FGFR2 (P-value¼0.0270). These results suggest that the FGFR2 polymorphism affects the variation in hair thickness in Asia through alteration in the expression level of FGFR2. Keywords: Asian; association; expression; FGFR2; hair morphology; hair thickness; population differentiation; rs4752566 INTRODUCTIONHair morphology is one of the most divergent traits among human populations. Africans and Melanesians have twisted hair, and Asians have thicker hair than people of the other continents. 1 To discover genes involved in human hair morphology, 21 candidate genes were previously picked up based on their functions and genetic differentiation between populations. Among these candidate genes, a nonsynonymous single nucleotide polymorphism (SNP) in ectodysplasin A receptor (EDAR), EDAR 1540T/C (rs3827760), which is highly differentiated between Asian (HapMap-CHB+JPT) and other populations (YRI and CEU), was found to be strongly associated with hair fiber thickness. 2,3 In addition, the chromosomal region of the EDAR gene showed a strong signature of recent positive selection in East Asian populations 2,4-9 These results led to the conclusion that EDAR is a major genetic determinant of Asian hair thickness and is likely to play an important role in adaptation to the local environments of East Asia.

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EDA2R Is Associated with Androgenetic Alopecia

Cited by 86 publications

References 20 publications

Prediction of male-pattern baldness from genotypes

Prediction of male-pattern baldness from genotypes

Population Differentiation as an Indicator of Recent Positive Selection in Humans: An Empirical Evaluation

FGFR2 is associated with hair thickness in Asian populations

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