A whole-genome reference panel of 14,393 individuals for East Asian populations accelerates discovery of rare functional variants.

Underrepresentation of non-European (EUR) populations hinders growth of global precision medicine. Resources such as imputation reference panels that match the study population are necessary to find low-frequency variants with substantial effects. We created a reference panel consisting of 14,393 whole-genome sequences including more than 11,000 Asian individuals. Genome-wide association studies were conducted using the reference panel and a population-specific genotype array of 72,298 subjects for eight phenotypes. This panel yields improved imputation accuracy of rare and low-frequency variants within East Asian populations compared with the largest reference panel. Thirty-nine previously unidentified associations were found, and more than half of the variants were East Asian specific. We discovered genes with rare protein-altering variants, including LTBP1 for height and GPR75 for body mass index, as well as putative regulatory mechanisms for rare noncoding variants with cell type-specific effects. We suggest that this dataset will add to the potential value of Asian precision medicine.

Acquired Resistance Mechanism of EGFR Kinase Domain Duplication to EGFR TKIs in Non-Small Cell Lung Cancer.

PURPOSE: Epidermal growth factor receptor kinase domain duplication (EGFR-KDD) is a rare and poorly understood oncogenic mutation in non-small cell lung cancer (NSCLC). We aimed to investigate the acquired resistance mechanism of EGFR-KDD against EGFR-TKIs. MATERIALS AND METHODS: We identified EGFR-KDD in tumor tissue obtained from a patient with stage IV lung adenocarcinoma and established the patient-derived cell line SNU-4784. We also established several EGFR-KDD Ba/F3 cell lines: EGFR-KDD wild type (EGFR-KDDWT), EGFR-KDD domain 1 T790M (EGFR-KDDD1T), EGFR-KDD domain 2 T790M (EGFR-KDDD2T), and EGFR-KDD both domain T790M (EGFR-KDDBDT). We treated the cells with EGFR tyrosine kinase inhibitors (TKIs) and performed cell viability assays, immunoblot assays, and ENU (N-ethyl-N-nitrosourea) mutagenesis screening. RESULTS: In cell viability assays, SNU-4784 cells and EGFR-KDDWT Ba/F3 cells were sensitive to 2nd generation and 3rd generation EGFR TKIs. In contrast, the T790M-positive EGFR-KDD Ba/F3 cell lines (EGFR-KDDT790M) were only sensitive to 3rd generation EGFR TKIs. In ENU mutagenesis screening, we identified the C797S mutation in kinase domain 2 of EGFR-KDDBDT Ba/F3 cells. Based on this finding, we established an EGFR-KDD domain 1 T790M/domain 2 cis-T790M+C797S (EGFR-KDDT/T+C) Ba/F3 model, which was resistant to EGFR TKIs and anti-EGFR monoclonal antibody combined with EGFR TKIs. CONCLUSION: Our study reveals that the T790M mutation in EGFR-KDD confers resistance to 1st and 2nd generation EGFR TKIs, but is sensitive to 3rd generation EGFR TKIs. In addition, we identified that the C797S mutation in kinase domain 2 of EGFR-KDDT790M mediates a resistance mechanism against 3rd generation EGFR TKIs.

NTRK and RET fusion-directed therapy in pediatric thyroid cancer yields a tumor response and radioiodine uptake.

BACKGROUNDMolecular characterization in pediatric papillary thyroid cancer (PTC), distinct from adult PTC, is important for developing molecularly targeted therapies for progressive radioiodine-refractory (131I-refractory) PTC.METHODSPTC samples from 106 pediatric patients (age range: 4.3-19.8 years; n = 84 girls, n = 22 boys) who were admitted to SNUH (January 1983-March 2020) were available for genomic profiling. Previous transcriptomic data from 125 adult PTC samples were used for comparison.RESULTSWe identified genetic drivers in 80 tumors: 31 with fusion oncogenes (RET in 21 patients, ALK in 6 patients, and NTRK1/3 in 4 patients); 47 with point mutations (BRAFV600E in 41 patients, TERTC228T in 2 patients [1 of whom had a coexisting BRAFV600E], and DICER1 variants in 5 patients); and 2 with amplifications. Fusion oncogene PTCs, which are predominantly detected in younger patients, were at a more advanced stage and showed more recurrent or persistent disease compared with BRAFV600E PTCs, which are detected mostly in adolescents. Pediatric fusion PTCs (in patients <10 years of age) had lower expression of thyroid differentiation genes, including SLC5A5, than did adult fusion PTCs. Two girls with progressive 131I-refractory lung metastases harboring a TPR-NTRK1 or CCDC6-RET fusion oncogene received fusion-targeted therapy; larotrectinib and selpercatinib decreased the size of the tumor and restored 125I radioiodine uptake. The girl with the CCDC6-RET fusion oncogene received 131I therapy combined with selpercatinib, resulting in a tumor response. In vitro 125I uptake and 131I clonogenic assays showed that larotrectinib inhibited tumor growth and restored radioiodine avidity.CONCLUSIONSIn pediatric patients with fusion oncogene PTC who have 131I-refractory advanced disease, selective fusion-directed therapy may restore radioiodine avidity and lead to a dramatic tumor response, underscoring the importance of molecular testing in pediatric patients with PTC.FUNDINGThe Ministry of Science, ICT and Future Planning (NRF-2016R1A2B4012417 and 2019R1A2C2084332); the Korean Ministry of Health and Welfare (H14C1277); the Ministry of Education (2020R1A6A1A03047972); and the SNUH Research Fund (04-2015-0830).TRIAL REGISTRATIONTwo patients received fusion-targeted therapy with larotrectinib (NCT02576431; NAVIGATE) or selpercatinib (LOXO-RET-18018).

Protective role of ABCA1 in ischemic preconditioning is mediated by downregulation of miR-33-5p and miR-135-5p.

Ischemic preconditioning (IPC) significantly reduces ischemia-reperfusion injury in the brain by inducing ischemic tolerance. Although emerging evidence suggests that microRNAs (miRNAs) contribute to the pathogenesis of brain ischemia and IPC-induced neuroprotection, the role of miRNAs and their underlying mechanisms are still unclear. IPC was induced in male C57BL/6 mice by brief bilateral common carotid artery occlusion. After 24 h, mice underwent transient middle cerebral artery occlusion followed by 3 h of reperfusion. Expression levels of messenger RNAs (mRNAs) and proteins were examined in the ipsilateral cortex, and mimics and inhibitors of selective miRNAs were transfected into Neuro-2a cells before oxygen-glucose deprivation (OGD). Post-IPC miRNA expression profiling identified neuroprotection-associated changes in miRNA expression in the ipsilateral cortex after ischemic stroke. Among them, miR-33-5p and miR-135b-5p were significantly downregulated by IPC. Inhibition of miR-33-5p and miR-135b-5p expression protected Neuro-2a cells from OGD-induced apoptosis. Inhibition of these two miRNAs significantly increased mRNA and protein levels of ATP-binding cassette subfamily A member 1 (ABCA1), and a binding assay showed that these two miRNAs showed specificity for Abca1 mRNA. Overexpression of ABCA1 decreased the Bax/Bcl2 mRNA ratio and activation of caspase-9 and caspase-3, whereas knockdown of ABCA1 expression increased the Bax/Bcl2 mRNA ratio and the percentage of Neuro-2a cells with a loss of mitochondrial membrane potential after OGD-treatment. In conclusion, ABCA1 expression is regulated by miR-33-5p and miR-135b-5p. Increased ABCA1 expression following IPC exerts a protective influence against cerebral ischemia via suppression of a mitochondria-dependent apoptosis pathway.

Phase II study of durvalumab and tremelimumab in pulmonary sarcomatoid carcinoma: KCSG-LU16-07.

BACKGROUND: Pulmonary sarcomatoid carcinoma (PSC) is rare with a poor outcome and is resistant to conventional cytotoxic chemotherapy. The efficacy and safety of durvalumab and tremelimumab for treating recurrent or metastatic PSCs were assessed by a nonrandomized, open-label, phase II study. METHODS: A total of 18 patients with recurrent or metastatic PSC received 1500 mg of durvalumab and 75 mg of tremelimumab every four weeks, followed by 750 mg of durvalumab every two weeks until the disease progressed, or an unacceptable toxicity level was reached. The primary endpoint was the objective response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. Genomic profiling of PSC by next-generation sequencing (NGS) and determination of peripheral blood lymphocyte subsets using flow cytometry were performed for exploratory analysis. RESULTS: A total of 15 out of 18 patients were evaluated for the analysis of the primary endpoint. At the data cutoff point, the ORR of 26.7% (95% confidence interval [CI]: 7.8-55.1) was achieved with the median follow-up duration of 12.0 months (range, 8.4-16.1). Median PFS and OS were 5.9 months (95% CI: 1.1-11.9) and 15.4 months (95% CI: 11.1-not reached), respectively. Treatment-related adverse events (AEs) of any grade were reported in 16 patients; the most common AEs were pruritus (n = 5), pneumonitis (n = 4), and rash (n = 4). Treatment was discontinued in two patients due to AEs of grade ≥ 3. CONCLUSIONS: Durvalumab and tremelimumab demonstrated clinical benefit with a prolonged survival and manageable toxicity profile in patients with recurrent or metastatic PSC.

A newly developed capture-based sequencing panel for genomic assay of lung cancer.

BACKGROUND: The increase in genetic alterations targeted by specific chemotherapy in lung cancer has led to the need for universal use of more comprehensive genetic testing, which has highlighted the development of a lung cancer diagnostic panel using next-generation sequencing. OBJECTIVE: We developed a hybridization capture-based massively parallel sequencing assay named Friendly, Integrated, Research-based, Smart and Trustworthy (FIRST)-lung cancer panel (LCP), and evaluated its performance. METHODS: FIRST-LCP comprises 64 lung cancer-related genes to test for various kinds of genetic alterations including single nucleotide variations (SNVs), insertions and deletions (indels), copy number variations (CNVs), and structural variations. To assess the performance of FIRST-LCP, we compiled test sets using HapMap samples or tumor cell lines with disclosed genetic information, and also tested our clinical lung cancer samples whose genetic alterations were known by conventional methods. RESULTS: FIRST-LCP accomplished high sensitivity (99.4%) and specificity (100%) of the detection of SNVs. High precision was also achieved, with intra- or inter-run concordance rate of 0.99, respectively. FIRST-LCP detected indels and CNVs close to the expected allele frequency and magnitude, respectively. Tests with samples from lung cancer patients also identified all SNVs, indels and fusions. CONCLUSION: Based on the current state of the art, continuous application of the panel design and analysis pipeline following up-to-date knowledge could ensure precision medicine for lung cancer patients.

A population-specific low-frequency variant of SLC22A12 (p.W258*) explains nearby genome-wide association signals for serum uric acid concentrations among Koreans.

Prolonged hyperuricemia is a cause of gout and an independent risk factor for chronic health conditions including diabetes and chronic kidney diseases. Genome-wide association studies (GWASs) for serum uric acid (SUA) concentrations have repeatedly confirmed genetic loci including those encoding uric acid transporters such as ABCG2 and SLC9A2. However, many single nucleotide polymorphisms (SNPs) found in GWASs have been common variants with small effects and unknown functions. In addition, there is still much heritability to be explained. To identify the causative genetic variants for SUA concentrations in Korean subjects, we conducted a GWAS (1902 males) and validation study (2912 males and females) and found four genetic loci reaching genome-wide significance on chromosomes 4 (ABCG2) and 11 (FRMD8, EIF1AD and SLC22A12-NRXN2). Three loci on chromosome 11 were distributed within a distance of 1.3 megabases and they were in weak or moderate linkage disequilibrium (LD) states (r2 = 0.02-0.68). In a subsequent association analysis on the GWAS loci of chromosome 11 using closely positioned markers derived from whole genome sequencing data, the most significant variant to be linked with the nearby GWAS signal was rs121907892 (c.774G>A, p.W258*) of the SLC22A12 gene. This variant, and each of the three GWAS SNPs, were in LD (r2 = 0.06-0.32). The strength of association of SNPs with SUA concentration (negative logarithm of P-values) and the genetic distance (r2 of LD) between rs121907892 and the surrounding SNPs showed a quantitative correlation. This variant has been found only in Korean and Japanese subjects and is known to lower the SUA concentration in the general population. Thus, this low-frequency variant, rs121907892, known to regulate SUA concentrations in previous studies, is responsible for the nearby GWAS signals.

Predominant DICER1 Pathogenic Variants in Pediatric Follicular Thyroid Carcinomas.

Background: Pediatric thyroid cancer has characteristics that are distinct from adulthood thyroid cancer. Due to its very low prevalence, little is known about the genetic characteristics of pediatric follicular thyroid cancer (FTC). Methods: We investigated genetic alterations in tumor tissues from 15 patients aged <20 years (median: 14.3 years; range: 2.4 - 19.0 years) using multifaceted approaches. Whole-exome sequencing, targeted next-generation sequencing using a cancer gene panel, and Sanger sequencing of the major exons of the H/K/N-RAS and DICER1 genes and the promoter region of the TERT gene were performed. Normal tissues or blood of patients with DICER1- or PTEN-positive tumors was also evaluated to determine whether the variant is germ line. Results: The median tumor size was 3.1 cm (range: 0.6 - 6.4 cm). Four patients exhibited angioinvasion and one extensive capsular invasion; none showed evidence of disease over a median of 8.1 years. Eight patients (53.3%) had DICER1 variants, including four with DICER1 syndrome (three patients were <10 years of age). One patient had a germ line PTEN frameshift variant with the diagnosis of PTEN hamartoma tumor syndrome. One patient had a PAX8/PPARγ rearrangement, and two patients had no genetic driver alteration other than multiple loss of heterozygosity with or without copy number alterations in their tumors. No RAS or TERT variants were found. Nodular hyperplasia and follicular adenoma (FA) coexisted in DICER1 variant-positive FTCs more frequently than variant-negative FTCs (p = 0.026). All DICER1 variant-positive FTCs had a somatic missense variant at metal binding sites (six at codon p.E1813 and two at codon p.D1709) within the RNase IIIb domain; seven had other missense, nonsense, or frameshift variants in the DICER1 gene. Six coexisting FAs of two patients with DICER1 syndrome (three of each) had additional somatic variants at metal binding sites within the RNase IIIb domain (codon p.E1705, p.D1709, p.D1810, or p.E1813), different from each other and from the indexed FTC tumor. Conclusions: Pediatric FTCs have distinct genomic alterations and pathogenesis compared with adults, particularly those characterized by DICER1 variants. The DICER1 variant should be considered in pediatric FTCs, especially in cases <10 years of age. In all DICER1 variant-positive FTCs and FAs, recurrent hotspot variants were found at metal binding sites within the RNase IIIb domain, suggesting they impact tumorigenesis.

Genomic Landscape of Young-Onset Bladder Cancer and Its Prognostic Implications on Adult Bladder Cancer.

Due to the rare occurrence of young-onset bladder cancer (YBC), its genomic characteristics remain largely unknown. Twenty-nine biopsy-proven YBC cases were collected using a nation-wide search for bladder cancer diagnosed at 20 years or younger. Whole exome sequencing and RNA sequencing were carried out in 21 and 11 cases, respectively, and compared with those of adult bladder cancer (ABC) cases obtained from public databases. Almost all YBCs were low grade, non-invasive papillary tumors. YBC had a low mutation burden and less complex copy number alterations. All cases harbored putative driver mutations. Mutations were most commonly found in HRAS (10 cases), with a preference for exon 5. FGFR3 gene fusions were noted with various partner genes (7 cases). The alterations on HRAS and FGFR3 occurred in a mutually exclusive manner. Others included KRAS mutations (2 cases), chromosomes 4p and 10q arm-level deletions (1 case), and ERCC2 mutation (1 case). There were no point mutations in TP53 and FGFR3. The gene expression profiles of YBC were similar to those of the ABC group with good prognosis. None of the YBCs and ABCs with YBC-like mutations showed progression to muscle-invasive tumors. Our results suggest that bladder cancer with YBC-like mutations represents an indolent bladder tumor, regardless of age.

Clinicopathological and molecular analysis of multinodular and vacuolating neuronal tumors of the cerebrum.

Multinodular and vacuolating neuronal tumor (MVNT) of the cerebrum is a recently recognized rare neuronal tumor, and its pathogenesis is unclear. We analyzed 7 cases of histologically typical MVNT: 6 were adults (mean age, 43.0 years [range, 23-56 years]) and 1 was a child (age, 10 years). The most common symptoms were seizures (n = 4) and headache (n = 2). The tumors were supratentorial (temporal, 5; frontal lobes, 2) in origin as reported. Vacuolated tumor cells were robustly positive for α-INA and Olig2 and at least partly positive for synaptophysin and MAP2, but negative for Neu-N, nestin and CD34. GFAP and vimentin were expressed in reactive astrocytes but not in tumor cells. Negative results were obtained for p53, IDH-1, BRAFV600E, H3 K27M, EGFR, Lin28A, and L1CAM. ATRX, BRG1, INI-1, and TMHH were retained. The Ki-67 labeling index was very low (<1%), and pHH3 revealed no mitotic figure. Ultrastructural features of tumor cells were comparable with those of immature neuronal cells, with several intracytoplasmic myelin-like autophagosomes and pericellular vacuolization. No IDH1/IDH2 and BRAFV600E mutations were found upon direct sequencing. Whole-exome sequencing revealed FGFR2-ZMYND11 gene fusion in 1 case. After gross total resection, all patients were alive without seizures. There was no tumor recurrence during an average period of 68 months (range, 23-101 months). The analysis of 7 typical cases of MVNT suggested that these lesions may be clonal tumors because FGFR2-ZMYND11 fusion was found (1 case).

Genome-Wide Association Study Reveals Distinct Genetic Susceptibility of Thyroid Nodules From Thyroid Cancer.

Context: Thyroid nodules are very common, and 7% to 15% of them are diagnosed as thyroid cancer. However, the inherited genetic risk factors for thyroid nodules and their associations with thyroid cancer remain unknown. Objective: To identify the genetic variants associated with susceptibility to thyroid nodules in comparison with thyroid cancer. Design and Setting: We performed a three-stage genome-wide association study for thyroid nodules. The discovery stage involved a genome-wide scan of 811 subjects with thyroid nodules and 691 subjects with a normal thyroid from a population-based cohort. Replication studies were conducted in an additional 1981 cases and 3100 controls from the participants of a health checkup. We also performed expression quantitative trait loci analysis of public data. Results: The most robust association was observed in TRPM3 (rs4745021) in the joint analysis (OR, 1.26; P = 6.12 × 10-8) and meta-analysis (OR, 1.28; P = 2.11 × 10-8). Signals at MBIP/NKX2-1 were replicated but did not reach genome-wide significance in the joint analysis (rs2415317, P = 4.62 × 10-5; rs944289, P = 8.68 × 10-5). The expression quantitative trait loci analysis showed that TRPM3 expression was associated with the rs4745021 genotype in thyroid tissues. Conclusions: To the best of our knowledge, we have performed the first genome-wide association study of thyroid nodules and identified a susceptibility locus associated with thyroid nodules, suggesting that thyroid nodules have a genetic predisposition distinct from that of thyroid cancer.

Genome-wide association and expression quantitative trait loci studies identify multiple susceptibility loci for thyroid cancer.

Thyroid cancer is the most common cancer in Korea. Several susceptibility loci of differentiated thyroid cancer (DTC) were identified by previous genome-wide association studies (GWASs) in Europeans only. Here we conducted a GWAS and a replication study in Koreans using a total of 1,085 DTC cases and 8,884 controls, and validated these results using expression quantitative trait loci (eQTL) analysis and clinical phenotypes. The most robust associations were observed in the NRG1 gene (rs6996585, P=1.08 × 10-10) and this SNP was also associated with NRG1 expression in thyroid tissues. In addition, we confirmed three previously reported loci (FOXE1, NKX2-1 and DIRC3) and identified seven novel susceptibility loci (VAV3, PCNXL2, INSR, MRSB3, FHIT, SEPT11 and SLC24A6) associated with DTC. Furthermore, we identified specific variants of DTC that have different effects according to cancer type or ethnicity. Our findings provide deeper insight into the genetic contribution to thyroid cancer in different populations.

Genome-Wide Association Study of Bone Mineral Density in Korean Men.

Osteoporosis is a medical condition of global concern, with increasing incidence in both sexes. Bone mineral density (BMD), a highly heritable trait, has been proven a useful diagnostic factor in predicting fracture. Because medical information is lacking about male osteoporotic genetics, we conducted a genome-wide association study of BMD in Korean men. With 1,176 participants, we analyzed 4,414,664 single nucleotide polymorphisms (SNPs) after genomic imputation, and identified five SNPs and three loci correlated with bone density and strength. Multivariate linear regression models were applied to adjust for age and body mass index interference. Rs17124500 (p = 6.42 × 10(-7)), rs34594869 (p = 6.53 × 10(-7)) and rs17124504 (p = 6.53 × 10(-7)) in 14q31.3 and rs140155614 (p = 8.64 × 10(-7)) in 15q25.1 were significantly associated with lumbar spine BMD (LS-BMD), while rs111822233 (p = 6.35 × 10(-7)) was linked with the femur total BMD (FT-BMD). Additionally, we analyzed the relationship between BMD and five genes previously identified in Korean men. Rs61382873 (p = 0.0009) in LRP5, rs9567003 (p = 0.0033) in TNFSF11 and rs9935828 (p = 0.0248) in FOXL1 were observed for LS-BMD. Furthermore, rs33997547 (p = 0.0057) in ZBTB and rs1664496 (p = 0.0012) in MEF2C were found to influence FT-BMD and rs61769193 (p = 0.0114) in ZBTB to influence femur neck BMD. We identified five SNPs and three genomic regions, associated with BMD. The significance of our results lies in the discovery of new loci, while also affirming a previously significant locus, as potential osteoporotic factors in the Korean male population.

The demographic changes of menopausal and geripausal women in Korea.

BACKGROUND: Osteoporosis and resultant fracture seems to be the most common skeletal disease, affecting female exclusively. Osteoporosis increases exponentially with menopause and age. Therefore the demographic data seems to be the most important & fundamental for the study of osteoporosis epidemiology. METHODS: This study was to analyzed population projection from 1960 to 2060. We evaluated the demographic change of female, postmenopausal and elderly geripausal population in South Korea using Korean statistical information service database as basic fundamental data for osteoporosis epidemiology. RESULTS: According to population projection, the total female population will be exceeds the total male population since 2015 and maximize up to 2030. In 2030, nearly half of female will become postmenopausal and one fourth of women elderly will be geripausal. Of total female population in 2060, the proportion of postmenopausal women will be increased up to 59.8%. CONCLUSIONS: According to population projection in South Korea, six of ten women in 2060 will be postmenopausal and seven of ten postmenopausal women geripausal. As expected to increase proportion of elderly women, dramatic rise of osteoporosis and osteoporotic fracture also expected. Health providers pay more attention to postmenopausal and geripausal women health care.

Heritabilities of facial measurements and their latent factors in korean families.

Genetic studies on facial morphology targeting healthy populations are fundamental in understanding the specific genetic influences involved; yet, most studies to date, if not all, have been focused on congenital diseases accompanied by facial anomalies. To study the specific genetic cues determining facial morphology, we estimated familial correlations and heritabilities of 14 facial measurements and 3 latent factors inferred from a factor analysis in a subset of the Korean population. The study included a total of 229 individuals from 38 families. We evaluated a total of 14 facial measurements using 2D digital photographs. We performed factor analysis to infer common latent variables. The heritabilities of 13 facial measurements were statistically significant (p < 0.05) and ranged from 0.25 to 0.61. Of these, the heritability of intercanthal width in the orbital region was found to be the highest (h (2) = 0.61, SE = 0.14). Three factors (lower face portion, orbital region, and vertical length) were obtained through factor analysis, where the heritability values ranged from 0.45 to 0.55. The heritability values for each factor were higher than the mean heritability value of individual original measurements. We have confirmed the genetic influence on facial anthropometric traits and suggest a potential way to categorize and analyze the facial portions into different groups.

Gene mapping study for constitutive skin color in an isolated Mongolian population.

To elucidate the genes responsible for constitutive human skin color, we measured the extent of skin pigmentation in the buttock, representative of lifelong non-sun-exposed skin, and conducted a gene mapping study on skin color in an isolated Mongolian population composed of 344 individuals from 59 families who lived in Dashbalbar, Mongolia. The heritability of constitutive skin color was 0.82, indicating significant genetic association on this trait. Through the linkage analysis using 1,039 short tandem repeat (STR) microsatellite markers, we identified a novel genomic region regulating constitutive skin color on 11q24.2 with an logarithm of odds (LOD) score of 3.39. In addition, we also found other candidate regions on 17q23.2, 6q25.1, and 13q33.2 (LOD ≥ 2). Family-based association tests on these regions with suggestive linkage peaks revealed ten and two significant single nucleotide polymorphisms (SNPs) on the linkage regions of chromosome 11 and 17, respectively. We were able to discover four possible candidate genes that would be implicated to regulate human skin color: ETS1, UBASH3B, ASAM, and CLTC.

Linkage and association scan for tanning ability in an isolated Mongolian population.

Tanning ability is important, because it represents the ability of the skin to protect itself against ultraviolet (UV) radiation. Here, we sought to determine genetic regions associated with tanning ability. Skin pigmentation was measured at the outer forearm and buttock areas to represent facultative and constitutive skin color, respectively. In our study population consisting of isolated Mongolian subjects, with common histories of environmental UV exposure during their nomadic life, facultative skin color adjusted by constitutive skin color was used to indicate tanning ability. Through linkage analysis and family-based association tests of 345 Mongolian subjects, we identified 2 potential linkage regions regulating tanning ability on 5q35.3 and 12q13.2, having 6 and 7 significant single nucleotide polymorphisms (SNPs), respectively. Those significant SNPs were located in or adjacent to potential candidate genes related to tanning ability: GRM6, ATF1, WNT1, and SILV/Pmel17.

Genome-wide linkage analysis for ocular and nasal anthropometric traits in a Mongolian population.

Anthropometric traits for eyes and nose are complex quantitative traits influenced by genetic and environmental factors. To date, there have been few reports on the contribution of genetic influence to these traits in Asian populations. The aim of this study was to determine the genetic effect and quantitative trait locus (QTL) of seven traits eyes- and nose-related anthropometric measurements in an isolated Mongolian population. Frontal and lateral photographs were obtained from 1,014 individuals (434 males and 580 females) of Mongolian origin. A total of 349 short tandem repeat markers on 22 autosomes were genotyped for each individual. Heritability estimates of the seven ocular and nasal traits, adjusted for significant covariates, ranged from 0.48 to 0.90, providing evidence for a genetic influence. Variance-component linkage analyses revealed 10 suggestive linkage signals on 5q34 (LOD=3.2), 18q12.2 (LOD=2.7), 5q15 (LOD=2.0), 9q34.2 (LOD=1.9), 5q34 (LOD=1.9), 17q22 (LOD=1.9), 13q33.3 (LOD=2.7), 1q36.22 (LOD=1.9), 4q32.1 (LOD=2.1) and 15q22.31 (LOD=2.9). Our study provides the first evidence that genetics influences nasal and ocular traits in a Mongolian population. Additional collaborative efforts will further extend our understanding of the link between genetic factors and human anthropometric traits.

Analysis of genetic and non-genetic factors that affect the QTc interval in a Mongolian population: the GENDISCAN study.

The QTc interval is a complex quantitative trait and a strong prognostic indicator of cardiovascular mortality in general, healthy people. The aim of this study was to identify non-genetic factors and quantitative trait loci that govern the QTc interval in an isolated Mongolian population. We used multiple regression analysis to determine the relationship between the QTc interval and non-genetic factors including height, blood pressure, and the plasma lipid level. Whole genome linkage analyses were performed to reveal quantitative trait loci for the QTc interval with 349 microsatellite markers from 1,080 Mongolian subjects. Among many factors previously known for association with the QTc interval, age, sex, heart rate, QRS duration of electrocardiogram and systolic blood pressure were also found to have influence on the QTc interval. A genetic effect for the QTc interval was identified based on familial correlation with a heritability value of 0.31. In a whole genome linkage analysis, we identified the four potential linkage regions 7q31-34, 5q21, 4q28, and 2q36.