Human Genetics (HUM GENET )

Publisher: Springer Verlag

Description

Human Genetics is a monthly journal publishing original and timely articles on all aspects of human genetics. The Journal welcomes articles in the areas of Gene structure and organization Gene expression Mutation detection and analysis Linkage analysis and genetic mapping Physical mapping Cytogenetics and Genomic Imaging Genome structure and organisation Disease association studies Molecular diagnostics Genetic epidemiology Evolutionary genetics Developmental genetics Genotype-phenotype relationships Molecular genetics of tumorigenesis Genetics of complex diseases and epistatic interactions and Bioinformatics. Articles reporting animal models relevant to human biology or disease are also welcome. Preference will be given to those articles which address clinically relevant questions or which provide new insights into human biology. Unless they report entirely novel and unusual aspects of a topic clinical case reports cytogenetic case reports papers on descriptive population genetics articles dealing with the frequency of polymorphisms or additional mutations within genes in which numerous lesions have already been described will normally not be accepted. The Journal will not normally consider for publication manuscripts that report merely the isolation map position structure and tissue expression profile of a gene of unknown function unless the gene is of unusual interest or is a candidate gene involved in a human trait or disorder. Data on novel pathological mutations may be submitted to Human Genetics Online the electronic mutation data submission system administered by Springer-Verlag (

Impact factor 4.52

  • Hide impact factor history
     
    Impact factor
  • 5-year impact
    4.49
  • Cited half-life
    9.20
  • Immediacy index
    1.27
  • Eigenfactor
    0.02
  • Article influence
    1.81
  • Website
    Human Genetics website
  • Other titles
    Human genetics (Online), Hum genet
  • ISSN
    0340-6717
  • OCLC
    41232248
  • Material type
    Document, Periodical, Internet resource
  • Document type
    Internet Resource, Computer File, Journal / Magazine / Newspaper

Publisher details

Springer Verlag

  • Pre-print
    • Author can archive a pre-print version
  • Post-print
    • Author can archive a post-print version
  • Conditions
    • Author's pre-print on pre-print servers such as arXiv.org
    • Author's post-print on author's personal website immediately
    • Author's post-print on any open access repository after 12 months after publication
    • Publisher's version/PDF cannot be used
    • Published source must be acknowledged
    • Must link to publisher version
    • Set phrase to accompany link to published version (see policy)
    • Articles in some journals can be made Open Access on payment of additional charge
  • Classification
    ​ green

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Silver–Russell syndrome (SRS) is a clinically heterogeneous disorder characterised by severe in utero growth restriction and poor postnatal growth, body asymmetry, irregular craniofacial features and several additional minor malformations. The aetiology of SRS is complex and current evidence strongly implicates imprinted genes. Approximately, half of all patients exhibit DNA hypomethylation at the H19/IGF2 imprinted domain, and around 10 % have maternal uniparental disomy of chromosome 7. We measured DNA methylation in 18 SRS patients at >485,000 CpG sites using DNA methylation microarrays. Using a novel bioinformatics methodology specifically designed to identify subsets of patients with a shared epimutation, we analysed methylation changes genome-wide as well as at known imprinted regions to identify SRS-associated epimutations. Our analysis identifies epimutations at the previously characterised domains of H19/IGF2 and at imprinted regions on chromosome 7, providing proof of principle that our methodology can detect DNA methylation changes at imprinted loci. In addition, we discovered two novel epimutations associated with SRS and located at imprinted loci previously linked to relevant mouse and human phenotypes. We identify RB1 as an additional imprinted locus associated with SRS, with a region near the RB1 differentially methylated region hypermethylated in 13/18 (~70 %) patients. We also report 6/18 (~33 %) patients were hypermethylated at a CpG island near the ANKRD11 gene. We do not observe consistent co-occurrence of epimutations at multiple imprinted loci in single SRS individuals. SRS is clinically heterogeneous and the absence of multiple imprinted loci epimutations reflects the heterogeneity at the molecular level. Further stratification of SRS patients by molecular phenotypes might aid the identification of disease causes.
    Human Genetics 01/2015;
  • [Show abstract] [Hide abstract]
    ABSTRACT: To the editor,Heo et al. (2014) recently reported male-specific associations between hypertension and 6 SNPs [rs2093395 (TREML2), rs17249754 (ATP2B1), rs12229654 (MYL2), rs3782889 (MYL2), rs11066280 (C12orf51), rs2072134 (OAS3)] in two Korean cohorts with a total of 3,551 cases and 4,725 controls who were genotyped using the Affymetrix Genome-Wide Human SNP Array 6.0. Five of the six reported SNPs were claimed to show a male-specific association with hypertension. We question the validity of the findings.The main results of Heo et al. displayed in Table 2 of the article are weakened by two methodological aspects. First, the KARE data consist of two cohorts, one from rural Ansung and one from urban Ansan. In the non-genetic analysis, the variable indicating region is significantly associated with hypertension (p = 2.1 × 10−22) with an effect size of OR = 1.86 (1.64, 2.11) (main article, Table 1). However, this variable is not included in this analysis (‘‘… data were adjusted for age, se ...
    Human Genetics 01/2015;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Family history of diabetes is a major risk factor for type 2 diabetes (T2D), but whether this association derives from shared genetic or environmental factors is unclear. To address this question, we developed a statistical framework that models four components of variance, including known and unknown genetic and environmental factors, using a liability threshold model. Focusing on parental history, we simulated case-control studies with two first-degree relatives for each individual, assuming 50 % genetic similarity and a range of values of environmental similarity. By comparing the association of parental history with T2D in our simulations to case-control studies of T2D nested in the Nurses' Health Study and Health Professionals Follow-up Study, we estimate that first-degree relatives have a correlation of 23 % (95 % CI 15-27 %) in their environmental contribution to T2D liability and that this shared environment is responsible for 32 % (95 % CI 24-36 %) of the association between parental history and T2D, with the remainder due to shared genetics. Estimates are robust to varying model parameter values and our framework can be extended to different definitions of family history. In conclusion, we find that the association between parental history and T2D derives from predominately genetic but also environmental effects.
    Human Genetics 12/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: CDH13 encodes T-cadherin, a receptor for high molecular weight (HMW) adiponectin and low-density lipoprotein, promoting proliferation and migration of endothelial cells. Genome-wide association studies have mapped multiple variants in CDH13 associated with cardiometabolic traits (CMT) with variable effects across studies. We hypothesized that this heterogeneity might reflect interplay with DNA methylation within the region. Resequencing and EpiTYPER™ assay were applied for the HYPertension in ESTonia/Coronary Artery Disease in Czech (HYPEST/CADCZ; n = 358) samples to identify CDH13 promoter SNPs acting as methylation Quantitative Trait Loci (meQTLs) and to investigate their associations with CMT. In silico data were extracted from genome-wide DNA methylation and genotype datasets of the population-based sample Estonian Genome Center of the University of Tartu (EGCUT; n = 165). HYPEST-CADCZ meta-analysis identified a rare variant rs113460564 as highly significant meQTL for a 134-bp distant CpG site (P = 5.90 × 10(-6); β = 3.19 %). Four common SNPs (rs12443878, rs12444338, rs62040565, rs8060301) exhibited effect on methylation level of up to 3 neighboring CpG sites in both datasets. The strongest association was detected in EGCUT between rs8060301 and cg09415485 (false discovery rate corrected P value = 1.89 × 10(-30)). Simultaneously, rs8060301 showed association with diastolic blood pressure, serum high-density lipoprotein and HMW adiponectin (P < 0.005). Novel strong associations were identified between rare CDH13 promoter meQTLs (minor allele frequency <5 %) and HMW adiponectin: rs2239857 (P = 5.50 × 10(-5), β = -1,841.9 ng/mL) and rs77068073 (P = 2.67 × 10(-4), β = -2,484.4 ng/mL). Our study shows conclusively that CDH13 promoter harbors meQTLs associated with CMTs. It paves the way to deeper understanding of the interplay between DNA variation and methylation in susceptibility to common diseases.
    Human Genetics 12/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cytopenia during interferon-based (IFN-based) therapy for chronic hepatitis C (CHC) often necessitates reduction of doses of drugs and premature withdrawal from therapy resulting in poor response to treatment. To identify genetic variants associated with IFN-induced neutropenia, we conducted a genome-wide association study (GWAS) in 416 Japanese CHC patients receiving IFN-based therapy. Based on the results, we selected 192 candidate single nucleotide polymorphisms (SNPs) to carry out a replication analysis in an independent set of 404 subjects. The SNP rs2305482, located in the intron region of the PSMD3 gene on chromosome 17, showed a strong association when the results of GWAS and the replication stage were combined (OR = 2.18, P = 3.05 × 10(-7) in the allele frequency model). Logistic regression analysis showed that rs2305482 CC and neutrophil count at baseline were independent predictive factors for IFN-induced neutropenia (OR = 2.497, P = 0.0072 and OR = 0.998, P < 0.0001, respectively). Furthermore, rs2305482 genotype was associated with the doses of pegylated interferon (PEG-IFN) that could be tolerated in hepatitis C virus genotype 1-infected patients treated with PEG-IFN plus ribavirin, but not with treatment efficacy. Our results suggest that genetic testing for this variant might be useful for establishing personalized drug dosing in order to minimize drug-induced adverse events.
    Human Genetics 12/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Peer behaviour plays an important role in the development of social adjustment, though little is known about its genetic architecture. We conducted a twin study combined with a genome-wide complex trait analysis (GCTA) and a genome-wide screen to characterise genetic influences on problematic peer behaviour during childhood and adolescence. This included a series of longitudinal measures (parent-reported Strengths-and-Difficulties Questionnaire) from a UK population-based birth-cohort (ALSPAC, 4-17 years), and a UK twin sample (TEDS, 4-11 years). Longitudinal twin analysis (TEDS; N ≤ 7,366 twin pairs) showed that peer problems in childhood are heritable (4-11 years, 0.60 < twin-h (2) ≤ 0.71) but genetically heterogeneous from age to age (4-11 years, twin-r g = 0.30). N ≤ 5,608, TEDS: N ≤ 2,691) provided furthermore little support for the contribution of measured common genetic variants during childhood (4-12 years, 0.02<[Formula: see text] ≤ 0.11) though these influences become stronger in adolescence (13-17 years, 0.14<[Formula: see text] ≤ 0.27). A subsequent cross-sectional genome-wide screen in ALSPAC (N ≤ 6,000) focussed on peer problems with the highest GCTA-heritability (10, 13 and 17 years, 0.0002 < GCTA-P ≤ 0.03). Single variant signals (P ≤ 10(-5)) were followed up in TEDS (N ≤ 2835, 9 and 11 years) and, in search for autism quantitative trait loci, explored within two autism samples (AGRE: N Pedigrees = 793; ACC: N Cases = 1,453/N Controls = 7,070). There was, however, no evidence for association in TEDS and little evidence for an overlap with the autistic continuum. In summary, our findings suggest that problematic peer relationships are heritable but genetically complex and heterogeneous from age to age, with an increase in common measurable genetic variation during adolescence.
    Human Genetics 12/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Retinitis pigmentosa (RP) is a group of inherited retinal disorders characterized by progressive photoreceptor degeneration. An accurate molecular diagnosis is essential for disease characterization and clinical prognoses. A retinal capture panel that enriches 186 known retinal disease genes, including 55 known RP genes, was developed. Targeted next-generation sequencing was performed for a cohort of 82 unrelated RP cases from Northern Ireland, including 46 simplex cases and 36 familial cases. Disease-causing mutations were identified in 49 probands, including 28 simplex cases and 21 familial cases, achieving a solving rate of 60 %. In total, 65 pathogenic mutations were found, and 29 of these were novel. Interestingly, the molecular information of 12 probands was neither consistent with their initial inheritance pattern nor clinical diagnosis. Further clinical reassessment resulted in a refinement of the clinical diagnosis in 11 patients. This is the first study to apply next-generation sequencing-based, comprehensive molecular diagnoses to a large number of RP probands from Northern Ireland. Our study shows that molecular information can aid clinical diagnosis, potentially changing treatment options, current family counseling and management.
    Human Genetics 12/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: We previously identified a low-frequency (1.1 %) coding variant (G45R; rs200573126) in the adiponectin gene (ADIPOQ) which was the basis for a multipoint microsatellite linkage signal (LOD = 8.2) for plasma adiponectin levels in Hispanic families. We have empirically evaluated the ability of data from targeted common variants, exome chip genotyping, and genome-wide association study data to detect linkage and association to adiponectin protein levels at this locus. Simple two-point linkage and association analyses were performed in 88 Hispanic families (1,150 individuals) using 10,958 SNPs on chromosome 3. Approaches were compared for their ability to map the functional variant, G45R, which was strongly linked (two-point LOD = 20.98) and powerfully associated (p value = 8.1 × 10(-50)). Over 450 SNPs within a broad 61 Mb interval around rs200573126 showed nominal evidence of linkage (LOD > 3) but only four other SNPs in this region were associated with p values < 1.0 × 10(-4). When G45R was accounted for, the maximum LOD score across the interval dropped to 4.39 and the best p value was 1.1 × 10(-5). Linked and/or associated variants ranged in frequency (0.0018-0.50) and type (coding, non-coding) and had little detectable linkage disequilibrium with rs200573126 (r (2) < 0.20). In addition, the two-point linkage approach empirically outperformed multipoint microsatellite and multipoint SNP analysis. In the absence of data for rs200573126, family-based linkage analysis using a moderately dense SNP dataset, including both common and low-frequency variants, resulted in stronger evidence for an adiponectin locus than association data alone. Thus, linkage analysis can be a useful tool to facilitate identification of high-impact genetic variants.
    Human Genetics 12/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Copy number variation has emerged as an important cause of phenotypic variation, particularly in relation to some complex disorders. Autism spectrum disorder (ASD) is one such disorder, in which evidence is emerging for an etiological role for some rare penetrant de novo and rare inherited copy number variants (CNVs). De novo variation, however, does not always explain the familial nature of ASD, leaving a gap in our knowledge concerning the heritable genetic causes of this disorder. Extended pedigrees, in which several members have ASD, provide an opportunity to investigate inherited genetic risk factors. In this current study, we recruited 19 extended ASD pedigrees, and, using the Illumina HumanOmni2.5 BeadChip, conducted genome-wide CNV interrogation. We found no definitive evidence of an etiological role for segregating CNVs in these pedigrees, and no evidence that linkage signals in these pedigrees are explained by segregating CNVs. However, a small number of putative de novo variants were transmitted from BAP parents to their ASD offspring, and evidence emerged for a rare duplication CNV at 11p13.3 harboring two putative 'developmental/neuropsychiatric' susceptibility gene(s), GSTP1 and NDUFV1.
    Human Genetics 11/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in ANKRD11 have recently been reported to cause KBG syndrome, an autosomal dominant condition characterized by intellectual disability (ID), behavioral problems, and macrodontia. To understand the pathogenic mechanism that relates ANKRD11 mutations with the phenotype of KBG syndrome, we studied the cellular characteristics of wild-type ANKRD11 and the effects of mutations in humans and mice. We show that the abundance of wild-type ANKRD11 is tightly regulated during the cell cycle, and that the ANKRD11 C-terminus is required for the degradation of the protein. Analysis of 11 pathogenic ANKRD11 variants in humans, including six reported in this study, and one reported in the Ankrd11 (Yod/+) mouse, shows that all mutations affect the C-terminal regions and that the mutant proteins accumulate aberrantly. In silico analysis shows the presence of D-box sequences that are signals for proteasome degradation. We suggest that ANKRD11 C-terminus plays an important role in regulating the abundance of the protein, and a disturbance of the protein abundance due to the mutations leads to KBG syndrome.
    Human Genetics 11/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: In their original investigation Stern et al. reported an association of a single codon insertion in the PICALM gene (p.K599_L600insL) with familial subvalvular aortic stenosis (SAS) in Newfoundland dogs (Stern et al. 2014). The reported findings are the basis of a commercially sold genetic test intended to help dog breeders to reduce SAS disease prevalence. In this report, we will outline that the original investigation by Stern et al. is not well designed, misinterprets data, and consequently makes incorrect claims. Additionally, we report data from a replication study that does not show any association between the PICALM variant and SAS.In our opinion, the experimental data reported by Stern et al. do not support the conclusion of an association of the PICALM insertion with SAS. Stern et al. do not precisely define the assumed mode of inheritance, but describe a single family of 45 dogs, which supports previous older reports of a possible dominant pattern of inheritance with variable ...
    Human Genetics 11/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Heritability measures the proportion of phenotypic variation attributable to genetic factors. In addition to a shared nuclear genetic component, a number of additional variance components, such as spousal correlation, sibship, household and maternal effects, may have strong contributions to inter-individual phenotype variation. In humans, the confounding effects of these components on heritability have not been studied thoroughly. We sought to obtain unbiased heritability estimates for complex traits in the presence of multiple variance components and also to estimate the contributions of these variance components to complex traits. We compared regression and variance component methods to estimate heritability in simulations when additional variance components existed. We then revisited heritability for several traits in Framingham Heart Study (FHS) participants. Using simulations, we found that failure to account for or misclassification of necessary variance components yielded biased heritability estimates. The direction and magnitude of the bias varied depending on a variance structure and an estimation method. Using the best fitted models to account for necessary variance components, we found that heritability estimates for most FHS traits were overestimated, ranging from 4 to 47 %, when we compared models that considered necessary variance components to models that only considered familial relationships. Spousal correlation explained 14-36 % of phenotypic variation in several anthropometric and lifestyle traits. Maternal and sibling effects also contributed to phenotypic variation, ranging from 3 to 5 % and 4 to 7 %, respectively, in several anthropometric and metabolic traits. Our findings may explain, in part, the missing heritability for some traits.
    Human Genetics 11/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Endometrial cancer is the most common invasive gynaecological cancer in women, and relatively little is known about inherited risk factors for this disease. This is the first genome-wide study to explore the role of common and rare germline copy number variants (CNVs) in predisposition to endometrial cancer. CNVs were called from germline DNA of 1,209 endometrioid endometrial cancer cases and 528 cancer-unaffected female controls. Overall CNV load of deletions or DNA gains did not differ significantly between cases and controls (P > 0.05), but cases presented with an excess of rare germline deletions overlapping likely functional genomic regions including genes (P = 8 × 10(-10)), CpG islands (P = 1 × 10(-7)) and sno/miRNAs regions (P = 3 × 10(-9)). On average, at least one additional gene and two additional CpG islands were disrupted by rare deletions in cases compared to controls. The most pronounced difference was that over 30 sno/miRNAs were disrupted by rare deletions in cases for every single disruption event in controls. A total of 13 DNA repair genes were disrupted by rare deletions in 19/1,209 cases (1.6 %) compared to one gene in 1/528 controls (0.2 %; P = 0.007), and this increased DNA repair gene loss in cases persisted after excluding five individuals carrying CNVs disrupting mismatch repair genes MLH1, MSH2 and MSH6 (P = 0.03). There were 34 miRNA regions deleted in at least one case but not in controls, the most frequent of which encompassed hsa-mir-661 and hsa-mir-203. Our study implicates rare germline deletions of functional and regulatory regions as possible mechanisms conferring endometrial cancer risk, and has identified specific regulatory elements as candidates for further investigation.
    Human Genetics 11/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dental caries (tooth decay) is the most common chronic disease, worldwide, affecting most children and adults. Though dental caries is highly heritable, few caries-related genes have been discovered. We investigated whether 18 genetic variants in the group of non-amelogenin enamel matrix genes (AMBN, ENAM, TUFT1, and TFIP11) were associated with dental caries experience in 13 age- and race-stratified samples from six parent studies (N = 3,600). Linear regression was used to model genetic associations and test gene-by-fluoride interaction effects for two sources of fluoride: daily tooth brushing and home water fluoride concentration. Meta-analysis was used to combine results across five child and eight adult samples. We observed the statistically significant association of rs2337359 upstream of TUFT1 with dental caries experience via meta-analysis across adult samples (p < 0.002) and the suggestive association for multiple variants in TFIP11 across child samples (p < 0.05). Moreover, we discovered two genetic variants (rs2337359 upstream of TUFT1 and missense rs7439186 in AMBN) involved in gene-by-fluoride interactions. For each interaction, participants with the risk allele/genotype exhibited greater dental caries experience only if they were not exposed to the source of fluoride. Altogether, these results confirm that variation in enamel matrix genes contributes to individual differences in dental caries liability, and demonstrate that the effects of these genes may be moderated by protective fluoride exposures. In short, genes may exert greater influence on dental caries in unprotected environments, or equivalently, the protective effects of fluoride may obviate the effects of genetic risk alleles.
    Human Genetics 11/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: The cleft palate only (CPO) is a common congenital defect with complex etiology in humans. The molecular etiology of the CPO remains unknown. Here, we report a loss-of-function mutation in X-linked TBX22 gene (T-box 22) in a six-generation family of the CPO with obvious phenotypes of both cleft palate and hyper-nasal speech. We identify a functional -73G>A mutation in the promoter of TBX22, which is located at the core-binding site of transcription factor ETS-1 (v-ets avian erythroblastosis virus E26 oncogene homolog 1). Phylogenetic analysis showed that the sequence around the -73G>A mutation site is specific in primates. The mutation was detected in all five affected male members cosegregating with the affected phenotype and heterozygote occurred only in some unaffected females of the family, suggesting an X-linked transmission of the mutation in the family. The -73G>A variant is a novel single nucleotide mutation. Cell co-transfections indicated that ETS-1 could activate the TBX22 promoter. Moreover, EMSA and ChIP assays demonstrated that the allele A disrupts the binding site of ETS-1, thus markedly decreases the activity of the TBX22 promoter, which is likely to lead to the birth defect of the CPO without ankyloglossia. These results suggest that a loss-of-function mutation in the X-linked TBX22 promoter may cause the cleft palate through disruption of TBX22-ETS-1 pathway.
    Human Genetics 11/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Recent technological advances have transformed cancer genetics research. These advances have served as the basis for the generation of a number of richly annotated datasets relevant to the cancer geneticist. In addition, many of these technologies are now within reach of smaller laboratories to answer specific biological questions. Thus, one of the most pressing issues facing an experimental cancer biology research program in genetics is incorporating data from multiple sources to annotate, visualize, and analyze the system under study. Fortunately, there are several computational resources to aid in this process. However, a significant effort is required to adapt a molecular biology-based research program to take advantage of these datasets. Here, we discuss the lessons learned in our laboratory and share several recommendations to make this transition effective. This article is not meant to be a comprehensive evaluation of all the available resources, but rather highlight those that we have incorporated into our laboratory and how to choose the most appropriate ones for your research program.
    Human Genetics 10/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Gene-environment (G × E) interactions have been invoked to account, at least in part, for the gap between the known heritability of common human diseases and the phenotypic variation hitherto explained by genetic variants. Noteworthy in this context, a case-only (CO) design has been proposed in the past as a means to detect G × E interactions possibly more efficiently than by using classical case-control and cohort designs. So far, however, most CO studies have followed a candidate (or single) gene approach, and the genome-wide utility of the CO design is still more or less unknown. In particular, the way in which linkage disequilibrium (LD) impacts upon the chance to detect G × E interaction through the analysis of proxy markers has not been studied in much detail before. Therefore, we systematically assessed the power to indirectly detect a given G × E interaction through exploiting LD in a CO design. Our simulations revealed a strong relationship between LD and detection power that was subsequently validated in a real colorectal cancer data set.
    Human Genetics 10/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Keloids are benign dermal tumors that occur ~20 times more often in African versus Caucasian descent individuals. While most keloids occur sporadically, a genetic predisposition is supported by both familial aggregation of some keloids and the large differences in risk among populations. Yet, no well-established genetic risk factors for keloids have been identified. In this study, we conducted admixture mapping and whole-exome association using 478 African Americans (AAs) samples (122 cases, 356 controls) with exome genotyping data to identify regions where local ancestry associated with keloid risk. Logistic regression was used to evaluate associations under admixture peaks. A significant mapping peak was observed on chr15q21.2-22.3. This peak included NEDD4, a gene previously implicated in a keloid genome-wide association study (GWAS) of Japanese individuals later validated in a Chinese cohort. While we observed modest evidence for association with NEDD4, a more significant association was observed at (myosin 1E) MYO1E. A genome scan not including the 15q21-22 region also identified associations at MYO7A (rs35641839, odds ratio [OR] = 4.71, 95 % confidence interval [CI] 2.38-9.32, p = 8.34 × 10(-6)) at 11q13.5. The identification of SNPs in two myosin genes strongly associated with keloid formation suggests that an altered cytoskeleton contributes to the enhanced migratory and invasive properties of keloid fibroblasts. Our findings support the admixture mapping approach for the study of keloid risk, and indicate potentially common genetic elements on chr15q21.2-22.3 in causation of keloids in AAs, Japanese, and Chinese populations.
    Human Genetics 10/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: The prevalence of type 2 diabetes (T2D) is greater in populations of African descent compared to European-descent populations. Genetic risk factors may underlie the disparity in disease prevalence. Genome-wide association studies (GWAS) have identified >60 common genetic variants that contribute to T2D risk in populations of European, Asian, African and Hispanic descent. These studies have not comprehensively examined population differences in cumulative risk allele load. To investigate the relationship between risk allele load and T2D risk, 46 T2D single nucleotide polymorphisms (SNPs) in 43 loci from GWAS in European, Asian, and African-derived populations were genotyped in 1,990 African Americans (n = 963 T2D cases, n = 1,027 controls) and 1,644 European Americans (n = 719 T2D cases, n = 925 controls) ascertained and recruited using a common protocol in the southeast United States. A genetic risk score (GRS) was constructed from the cumulative risk alleles for each individual. In African American subjects, risk allele frequencies ranged from 0.024 to 0.964. Risk alleles from 26 SNPs demonstrated directional consistency with previous studies, and 3 SNPs from ADAMTS9, TCF7L2, and ZFAND6 showed nominal evidence of association (p < 0.05). African American individuals carried 38-67 (53.7 ± 4.0, mean ± SD) risk alleles. In European American subjects, risk allele frequencies ranged from 0.084 to 0.996. Risk alleles from 36 SNPs demonstrated directional consistency, and 10 SNPs from BCL11A, PSMD6, ADAMTS9, ZFAND3, ANK1, CDKN2A/B, TCF7L2, PRC1, FTO, and BCAR1 showed evidence of association (p < 0.05). European American individuals carried 38-65 (50.9 ± 4.4) risk alleles. African Americans have a significantly greater burden of 2.8 risk alleles (p = 3.97 × 10(-89)) compared to European Americans. However, GRS modeling showed that cumulative risk allele load was associated with risk of T2D in European Americans, but only marginally in African Americans. This result suggests that there are ethnic-specific differences in genetic architecture underlying T2D, and that these differences complicate our understanding of how risk allele load impacts disease susceptibility.
    Human Genetics 10/2014;