Androgenetic alopecia: identification of four genetic risk loci and evidence for the contribution of WNT signaling to its etiology.

The pathogenesis of androgenetic alopecia (AGA, male-pattern baldness) is driven by androgens, and genetic predisposition is the major prerequisite. Candidate gene and genome-wide association studies have reported that single-nucleotide polymorphisms (SNPs) at eight different genomic loci are associated with AGA development. However, a significant fraction of the overall heritable risk still awaits identification. Furthermore, the understanding of the pathophysiology of AGA is incomplete, and each newly associated locus may provide novel insights into contributing biological pathways. The aim of this study was to identify unknown AGA risk loci by replicating SNPs at the 12 genomic loci that showed suggestive association (5 × 10(-8)<P<10(-5)) with AGA in a recent meta-analysis. We analyzed a replication set comprising 2,759 cases and 2,661 controls of European descent to confirm the association with AGA at these loci. Combined analysis of the replication and the meta-analysis data identified four genome-wide significant risk loci for AGA on chromosomes 2q35, 3q25.1, 5q33.3, and 12p12.1. The strongest association signal was obtained for rs7349332 (P=3.55 × 10(-15)) on chr2q35, which is located intronically in WNT10A. Expression studies in human hair follicle tissue suggest that WNT10A has a functional role in AGA etiology. Thus, our study provides genetic evidence supporting an involvement of WNT signaling in AGA development.

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function.

INTRODUCTION: The antiretroviral drug efavirenz (EFV) is extensively metabolized into three primary metabolites: 8-hydroxy-EFV, 7-hydroxy-EFV and N-glucuronide-EFV. There is a wide interindividual variability in EFV plasma exposure, explained to a great extent by cytochrome P450 2B6 (CYP2B6), the main isoenzyme responsible for EFV metabolism and involved in the major metabolic pathway (8-hydroxylation) and to a lesser extent in 7-hydroxylation. When CYP2B6 function is impaired, the relevance of CYP2A6, the main isoenzyme responsible for 7-hydroxylation may increase. We hypothesize that genetic variability in this gene may contribute to the particularly high, unexplained variability in EFV exposure in individuals with limited CYP2B6 function. METHODS: This study characterized CYP2A6 variation (14 alleles) in individuals (N=169) previously characterized for functional variants in CYP2B6 (18 alleles). Plasma concentrations of EFV and its primary metabolites (8-hydroxy-EFV, 7-hydroxy-EFV and N-glucuronide-EFV) were measured in different genetic backgrounds in vivo. RESULTS: The accessory metabolic pathway CYP2A6 has a critical role in limiting drug accumulation in individuals characterized as CYP2B6 slow metabolizers. CONCLUSION: Dual CYP2B6 and CYP2A6 slow metabolism occurs at significant frequency in various human populations, leading to extremely high EFV exposure.

Toll-like receptor 2 (TLR2) polymorphisms are associated with reversal reaction in leprosy.

BACKGROUND: Leprosy is characterized by a spectrum of clinical manifestations that depend on the type of immune response against the pathogen. Patients may undergo immunological changes known as "reactional states" (reversal reaction and erythema nodosum leprosum) that result in major clinical deterioration. The goal of the present study was to assess the effect of Toll-like receptor 2 (TLR2) polymorphisms on susceptibility to and clinical presentation of leprosy. METHODS: Three polymorphisms in TLR2 (597C--&gt;T, 1350T--&gt;C, and a microsatellite marker) were analyzed in 431 Ethiopian patients with leprosy and 187 control subjects. The polymorphism-associated risk of developing leprosy, lepromatous (vs. tuberculoid) leprosy, and leprosy reactions was assessed by multivariate logistic regression models. RESULTS: The microsatellite and the 597C--&gt;T polymorphisms both influenced susceptibility to reversal reaction. Although the 597T allele had a protective effect (odds ratio [OR], 0.34 [95% confidence interval {CI}, 0.17-0.68]; P= .002 under the dominant model), homozygosity for the 280-bp allelic length of the microsatellite strongly increased the risk of reversal reaction (OR, 5.83 [95% CI, 1.98-17.15]; P= .001 under the recessive model). These associations were consistent among 3 different ethnic groups. CONCLUSIONS: These data suggest a significant role for TLR-2 in the occurrence of leprosy reversal reaction and provide new insights into the immunogenetics of the disease.

Association study of 182 candidate genes in anorexia nervosa.

We performed association studies with 5,151 SNPs that were judged as likely candidate genetic variations conferring susceptibility to anorexia nervosa (AN) based on location under reported linkage peaks, previous results in the literature (182 candidate genes), brain expression, biological plausibility, and estrogen responsivity. We employed a case-control design that tested each SNP individually as well as haplotypes derived from these SNPs in 1,085 case individuals with AN diagnoses and 677 control individuals. We also performed separate association analyses using three increasingly restrictive case definitions for AN: all individuals with any subtype of AN (All AN: n = 1,085); individuals with AN with no binge eating behavior (AN with No Binge Eating: n = 687); and individuals with the restricting subtype of AN (Restricting AN: n = 421). After accounting for multiple comparisons, there were no statistically significant associations for any individual SNP or haplotype block with any definition of illness. These results underscore the importance of large samples to yield appropriate power to detect genotypic differences in individuals with AN and also motivate complementary approaches involving Genome-Wide Association (GWA) studies, Copy Number Variation (CNV) analyses, sequencing-based rare variant discovery assays, and pathway-based analysis in order to make up for deficiencies in traditional candidate gene approaches to AN.

Genetics of essential tremor.

Essential tremor (ET) is a prevalent condition manifesting with progressive action tremor. Although ET was traditionally viewed as a sporadic disease, a significant proportion of cases report a positive family history of tremor. Autosomal dominant inheritance can be demonstrated in many families. Previously, genome-wide linkage studies in families mapped three loci for ET, hereditary essential tremor-1 (ETM1), ETM2 and ETM3. However, no causal mutation has been replicated in candidate genes within these loci, including dopamine D3 receptor (DRD3) and HS1-binding protein 3 (HS1BP3). Recently, the first genome-wide association study in ET followed by replication studies conducted in diverse populations identified a significant association between the leucine-rich repeat and Ig domain containing 1 gene (LINGO1) SNP rs9652490 and risk for ET Although further novel variants were indentified in LINGO1 and its paralog LINGO2 that may be associated with risk for ET, the pathogenic mechanisms involved remain elusive. Given the possibility that ET as a complex trait may be influenced by the combined effects of rare variants, novel high-throughput technologies sequencing all exons across the genome (exome sequencing) or the whole genome (genome sequencing) may become crucial in understanding/deciphering the genetic background of ET.

Genes mirror geography within Europe.

Understanding the genetic structure of human populations is of fundamental interest to medical, forensic and anthropological sciences. Advances in high-throughput genotyping technology have markedly improved our understanding of global patterns of human genetic variation and suggest the potential to use large samples to uncover variation among closely spaced populations. Here we characterize genetic variation in a sample of 3,000 European individuals genotyped at over half a million variable DNA sites in the human genome. Despite low average levels of genetic differentiation among Europeans, we find a close correspondence between genetic and geographic distances; indeed, a geographical map of Europe arises naturally as an efficient two-dimensional summary of genetic variation in Europeans. The results emphasize that when mapping the genetic basis of a disease phenotype, spurious associations can arise if genetic structure is not properly accounted for. In addition, the results are relevant to the prospects of genetic ancestry testing; an individual's DNA can be used to infer their geographic origin with surprising accuracy-often to within a few hundred kilometres.

How accurate is the current picture of human genetic variation?

Our understanding of the distribution of worldwide human genomic diversity has greatly increased over recent years thanks to the availability of large data sets derived from short tandem repeats (STRs), insertion deletion polymorphisms (indels) and single nucleotide polymorphisms (SNPs). A concern, however, is that the current picture of worldwide human genomic diversity may be inaccurate because of biases in the selection process of genetic markers (so-called 'ascertainment bias'). To evaluate this problem, we first compared the distribution of genomic diversity between these three types of genetic markers in the populations from the HGDP-CEPH panel for evidence of bias or incongruities. In a second step, using a very relaxed set of criteria to prevent the intrusion of bias, we developed a new set of unbiased STR markers and compared the results against those from available panels. Contrarily to recent claims, our results show that the STR markers suffer from no discernible bias, and can thus be used as a baseline reference for human genetic diversity and population differentiation. The bias on SNPs is moderate compared to that on the set of indels analysed, which we recommend should be avoided for work describing the distribution of human genetic diversity or making inference on human settlement history.

Association between variants of the leptin receptor gene (LEPR) and overweight: a systematic review and an analysis of the CoLaus study.

BACKGROUND: Three non-synonymous single nucleotide polymorphisms (Q223R, K109R and K656N) of the leptin receptor gene (LEPR) have been tested for association with obesity-related outcomes in multiple studies, showing inconclusive results. We performed a systematic review and meta-analysis on the association of the three LEPR variants with BMI. In addition, we analysed 15 SNPs within the LEPR gene in the CoLaus study, assessing the interaction of the variants with sex. METHODOLOGY/PRINCIPAL FINDINGS: We searched electronic databases, including population-based studies that investigated the association between LEPR variants Q223R, K109R and K656N and obesity- related phenotypes in healthy, unrelated subjects. We furthermore performed meta-analyses of the genotype and allele frequencies in case-control studies. Results were stratified by SNP and by potential effect modifiers. CoLaus data were analysed by logistic and linear regressions and tested for interaction with sex. The meta-analysis of published data did not show an overall association between any of the tested LEPR variants and overweight. However, the choice of a BMI cut-off value to distinguish cases from controls was crucial to explain heterogeneity in Q223R. Differences in allele frequencies across ethnic groups are compatible with natural selection of derived alleles in Q223R and K109R and of the ancient allele in K656N in Asians. In CoLaus, the rs10128072, rs3790438 and rs3790437 variants showed interaction with sex for their association with overweight, waist circumference and fat mass in linear regressions. CONCLUSIONS: Our systematic review and analysis of primary data from the CoLaus study did not show an overall association between LEPR SNPs and overweight. Most studies were underpowered to detect small effect sizes. A potential effect modification by sex, population stratification, as well as the role of natural selection should be addressed in future genetic association studies.

A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance.

Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.

Infantile spasms is associated with deletion of the MAGI2 gene on chromosome 7q11.23-q21.11.

Infantile spasms (IS) is the most severe and common form of epilepsy occurring in the first year of life. At least half of IS cases are idiopathic in origin, with others presumed to arise because of brain insult or malformation. Here, we identify a locus for IS by high-resolution mapping of 7q11.23-q21.1 interstitial deletions in patients. The breakpoints delineate a 500 kb interval within the MAGI2 gene (1.4 Mb in size) that is hemizygously disrupted in 15 of 16 participants with IS or childhood epilepsy, but remains intact in 11 of 12 participants with no seizure history. MAGI2 encodes the synaptic scaffolding protein membrane-associated guanylate kinase inverted-2 that interacts with Stargazin, a protein also associated with epilepsy in the stargazer mouse.

A missense mutation in myelin oligodendrocyte glycoprotein as a cause of familial narcolepsy with cataplexy.

Narcolepsy is a rare sleep disorder characterized by excessive daytime sleepiness and cataplexy. Familial narcolepsy accounts for less than 10% of all narcolepsy cases. However, documented multiplex families are very rare and causative mutations have not been identified to date. To identify a causative mutation in familial narcolepsy, we performed linkage analysis in the largest ever reported family, which has 12 affected members, and sequenced coding regions of the genome (exome sequencing) of three affected members with narcolepsy and cataplexy. We successfully mapped a candidate locus on chromosomal region 6p22.1 (LOD score ¼ 3.85) by linkage analysis. Exome sequencing identified a missense mutation in the second exon of MOG within the linkage region. A c.398C>G mutation was present in all affected family members but absent in unaffected members and 775 unrelated control subjects. Transient expression of mutant myelin oligodendrocyte glycoprotein (MOG) in mouse oligodendrocytes showed abnormal subcellular localization, suggesting an altered function of the mutant MOG. MOG has recently been linked to various neuropsychiatric disorders and is considered as a key autoantigen in multiple sclerosis and in its animal model, experimental autoimmune encephalitis. Our finding of a pathogenic MOG mutation highlights a major role for myelin and oligodendrocytes in narcolepsy and further emphasizes glial involvement in neurodegeneration and neurobehavioral disorders. [corrected].

Genome-wide association study for coronary artery calcification with follow-up in myocardial infarction.

BACKGROUND: Coronary artery calcification (CAC) detected by computed tomography is a noninvasive measure of coronary atherosclerosis, which underlies most cases of myocardial infarction (MI). We sought to identify common genetic variants associated with CAC and further investigate their associations with MI. METHODS AND RESULTS: Computed tomography was used to assess quantity of CAC. A meta-analysis of genome-wide association studies for CAC was performed in 9961 men and women from 5 independent community-based cohorts, with replication in 3 additional independent cohorts (n=6032). We examined the top single-nucleotide polymorphisms (SNPs) associated with CAC quantity for association with MI in multiple large genome-wide association studies of MI. Genome-wide significant associations with CAC for SNPs on chromosome 9p21 near CDKN2A and CDKN2B (top SNP: rs1333049; P=7.58×10(-19)) and 6p24 (top SNP: rs9349379, within the PHACTR1 gene; P=2.65×10(-11)) replicated for CAC and for MI. Additionally, there is evidence for concordance of SNP associations with both CAC and MI at a number of other loci, including 3q22 (MRAS gene), 13q34 (COL4A1/COL4A2 genes), and 1p13 (SORT1 gene). CONCLUSIONS: SNPs in the 9p21 and PHACTR1 gene loci were strongly associated with CAC and MI, and there are suggestive associations with both CAC and MI of SNPs in additional loci. Multiple genetic loci are associated with development of both underlying coronary atherosclerosis and clinical events.

The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.

Importance of IL28B gene polymorphisms in hepatitis C virus genotype 2 and 3 infected patients.

BACKGROUND & AIMS: Genetic variation in the interleukin 28B (IL28B) gene has been associated with the response to interferon-alfa/ribavirin therapy in hepatitis C virus (HCV) genotype 1-infected patients. The importance of three IL28B single nucleotide polymorphisms (rs8099917, rs12980275 and rs12979860) for HCV genotype 2/3-infected patients is unknown. METHODS: In patients with chronic hepatitis C genotype 2/3 (n=267), IL28B host genotypes (rs8099917, rs12980275 and rs12979860) were analyzed for associations with sustained virologic response (SVR) to antiviral therapy with (pegylated) interferon-alfa and ribavirin and with respect to epidemiological, biochemical, and virological parameters. For comparison, hepatitis C genotype 1 patients (n=378) and healthy controls (n=200) were included. RESULTS: The rs12979860 CC genotype, lower age, and genotype 2 were significantly associated with SVR in HCV genotype 2/3-infected patients (p=0.01, p=0.03 and p=0.03, respectively). No association was observed for rs8099917 and rs12980275. In addition, an SVR in patients with rapid virologic response (RVR) was associated with the rs12979860 CC genotype (p=0.05), while for non-RVR no association was found. Furthermore, a significant association with a higher baseline viral load was observed for all three IL28B genotypes in genotype 1/2/3-infected patients. Finally, increasing frequencies of the rs12979860 CC genotypes were observed in genotype 1- (33.9%), genotype 3- (38.9%), and genotype 2-infected (51.9%) patients in comparison with healthy controls (49.0%) (p<0.01). CONCLUSIONS: In genotype 2/3-infected patients, rs12979860 was significantly associated with SVR. The frequency of the rs12979860 CC genotype is lower in HCV genotype 1 vs. genotype 2/3 patients. All major IL28B genotypes are associated with HCV-RNA concentration.