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Six novel susceptibility Loci for early-onset androgenetic alopecia and their unexpected association with common diseases.

ABSTRACT: Androgenetic alopecia (AGA) is a highly heritable condition and the most common form of hair loss in humans. Susceptibility loci have been described on the X chromosome and chromosome 20, but these loci explain a minority of its heritable variance. We conducted a large-scale meta-analysis of seven genome-wide association studies for early-onset AGA in 12,806 individuals of European ancestry. While replicating the two AGA loci on the X chromosome and chromosome 20, six novel susceptibility loci reached genome-wide significance (p?=?2.62×10??-1.01×10?¹²). Unexpectedly, we identified a risk allele at 17q21.31 that was recently associated with Parkinson's disease (PD) at a genome-wide significant level. We then tested the association between early-onset AGA and the risk of PD in a cross-sectional analysis of 568 PD cases and 7,664 controls. Early-onset AGA cases had significantly increased odds of subsequent PD (OR?=?1.28, 95% confidence interval: 1.06-1.55, p?=?8.9×10?³). Further, the AGA susceptibility alleles at the 17q21.31 locus are on the H1 haplotype, which is under negative selection in Europeans and has been linked to decreased fertility. Combining the risk alleles of six novel and two established susceptibility loci, we created a genotype risk score and tested its association with AGA in an additional sample. Individuals in the highest risk quartile of a genotype score had an approximately six-fold increased risk of early-onset AGA [odds ratio (OR)?=?5.78, p?=?1.4×10???]. Our results highlight unexpected associations between early-onset AGA, Parkinson's disease, and decreased fertility, providing important insights into the pathophysiology of these conditions.

SUBMITTER: Li R

PROVIDER: S-EPMC3364959 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Six novel susceptibility Loci for early-onset androgenetic alopecia and their unexpected association with common diseases.

Li Rui R Brockschmidt Felix F FF Kiefer Amy K AK Stefansson Hreinn H Nyholt Dale R DR Song Kijoung K Vermeulen Sita H SH Kanoni Stavroula S Glass Daniel D Medland Sarah E SE Dimitriou Maria M Waterworth Dawn D Tung Joyce Y JY Geller Frank F Heilmann Stefanie S Hillmer Axel M AM Bataille Veronique V Eigelshoven Sibylle S Hanneken Sandra S Moebus Susanne S Herold Christine C den Heijer Martin M Montgomery Grant W GW Deloukas Panos P Eriksson Nicholas N Heath Andrew C AC Becker Tim T Sulem Patrick P Mangino Massimo M Vollenweider Peter P Spector Tim D TD Dedoussis George G Martin Nicholas G NG Kiemeney Lambertus A LA Mooser Vincent V Stefansson Kari K Hinds David A DA Nöthen Markus M MM Richards J Brent JB

PLoS genetics 20120531 5

Androgenetic alopecia (AGA) is a highly heritable condition and the most common form of hair loss in humans. Susceptibility loci have been described on the X chromosome and chromosome 20, but these loci explain a minority of its heritable variance. We conducted a large-scale meta-analysis of seven genome-wide association studies for early-onset AGA in 12,806 individuals of European ancestry. While replicating the two AGA loci on the X chromosome and chromosome 20, six novel susceptibility loci r ...[more]

PMID: 22693459

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Project description:BackgroundEarly-onset androgenetic alopecia (AGA) has been associated with various chronic conditions, including metabolic syndrome (MetS). Gaining a deep understanding of early-onset AGA may enable earlier intervention in individuals at high risks. This scoping review aims to explore the risk factors and etiology, associated conditions, and adverse effects on wellbeing in early-onset AGA.MethodsElectronic literature searches were conducted in MEDLINE, EMBASE and CENTRIAL. Eligible studies included case-control, cohort, cross-sectional, and meta-analysis studies. Selected studies needed to clearly define early-onset AGA cases or include only cases starting before the age of 40 and compare them with appropriate controls. The exclusion criteria comprised editorials, commentaries, case series, and non-systematic reviews, among others. Data extraction involved collecting study characteristics, methodologies, main outcomes, and findings. Descriptive tables were used to summarize key information and relevant variables when necessary.ResultsAmong the 65 eligible articles, 67.69% were case-control studies and 78.46% evaluated only male patients. "Early-onset" was defined as cases developing before the age of 30 years in 43.08% of the studies. The Hamilton-Norwood scale was the most frequently used method for evaluating the severity of alopecia in men (69.23%). Reported risk factors for early-onset AGA included a family history of AGA, cigarette smoking, unhealthy dietary habits, and a high body mass index. Early-onset AGA may also be associated with hormonal profiles, 5α-reductase enzyme activity, androgen receptor genes, and some susceptibility loci. Comorbidities investigated included MetS, cardiovascular disease, insulin resistance, dyslipidemia, and Parkinson's disease. Men with early-onset AGA may have reduced treatment efficacy with drug like rosuvastatin, metformin or lisinopril for dyslipidemia, prediabetes, or hypertension. Additionally, young men with AGA tended to suffer from psychological issues such as anxiety and low self-esteem compared to those without hair loss.ConclusionEarly-onset AGA is a complex condition with various risk factors and etiology, associated comorbidities, and potential implications for treatment response and psychological health.

Project description:The circulating concentrations of triglycerides, high density lipoprotein (HDL)?cholesterol, and low density lipoprotein (LDL)?cholesterol have a substantial genetic component, and the heritability of early?onset dyslipidemia might be expected to be higher compared with late?onset forms. In the present study, exome?wide association studies (EWASs) were performed for early?onset hypertriglyceridemia, hypo?HDL?cholesterolemia, and hyper?LDL?cholesterolemia, with the aim to identify genetic variants that confer susceptibility to these conditions in the Japanese population. A total of 8,073 individuals aged ?65 years were enrolled in the study. The EWASs for hypertriglyceridemia (2,664 cases and 5,294 controls), hypo?HDL?cholesterolemia (974 cases and 7,085 controls), and hyper?LDL?cholesterolemia (2,911 cases and 5,111 controls) were performed with Illumina Human Exome?12 v1.2 DNA Analysis BeadChip or Infinium Exome?24 v1.0 BeadChip arrays. The association of allele frequencies for 31,198, 31,133, or 31,175 single nucleotide polymorphisms (SNPs) to hypertriglyceridemia, hypo?HDL?cholesterolemia, or hyper?LDL?cholesterolemia, respectively, was examined with Fisher's exact test. To compensate for multiple comparisons of genotypes with each of the three conditions, Bonferroni's correction was applied for statistical significance of association. The results demonstrated that 25, 28 and 65 SNPs were significantly associated with hypertriglyceridemia, hypo?HDL?cholesterolemia and hyper?LDL?cholesterolemia, respectively. Multivariable logistic regression analysis with adjustment for age and sex revealed that all 25, 28 and 65 of these SNPs were significantly associated with hypertriglyceridemia, hypo?HDL?cholesterolemia and hyper?LDL?cholesterolemia, respectively. Following examination of the association of the identified SNPs to serum concentrations of triglycerides, HDL?cholesterol, or LDL?cholesterol, linkage disequilibrium of the SNPs, and results of previous genome?wide association studies, we newly identified chromosomal region 19p12 as a susceptibility locus for hypertriglyceridemia, eight loci (MOB3C?TMOD4, LPGAT1, EHD3, COL6A3, ZNF860?CACNA1D, COL6A5, DCLRE1C, ZNF77) for hypo?HDL?cholesterolemia, and three loci (KIAA0319?FAM65B, UBD, LOC105375015) for hyper?LDL?cholesterolemia. The present study thus identified 12 novel loci that may confer susceptibility to early?onset dyslipidemia. Determination of genotypes for the SNPs at these loci may prove informative for assessment of genetic risk for hypertriglyceridemia, hypo?HDL?cholesterolemia, or hyper?LDL?cholesterolemia in the Japanese population.

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Six novel susceptibility Loci for early-onset androgenetic alopecia and their unexpected association with common diseases.

Publications

Six novel susceptibility Loci for early-onset androgenetic alopecia and their unexpected association with common diseases.

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