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Objective: Although genome-wide association studies (GWAS) have substantially contributed to understanding the genetic architecture, unidentified variants for complex traits remain an issue. One of the efficient approaches is the improvement of the power of GWAS scan by weighting P values with prior linkage signals. Our objective was to identify the novel candidates for obesity in Asian populations by using genemapping strategies that combine linkage and association analyses., Design and Methods: To obtain linkage information for body mass index (BMI) and waist circumference (WC), we performed a multipoint genome-wide linkage study in an isolated Mongolian sample of 1,049 individuals from 74 families. Next, a family-based GWAS, which integrates within- and between-family components, was performed using the genotype data of 756 individuals of the Mongolian sample, and P values for association were weighted using linkage information obtained previously., Results: For both BMI (LOD = 3.3) and WC (LOD = 2.6), the highest linkage peak was discovered at chromosome 10q11.22. In family-based GWAS combined with linkage information, six single-nucleotide polymorphisms (SNPs) for BMI and five SNPs for WC reached a significant level of association (linkage weighted P < 1 × 10(-5) ). Of these, only one of the SNPs associated with WC (rs1704198) was replicated in 327 Korean families comprising 1,301 individuals. This SNP was located in the proximity of the prosperorelated homeobox 1 (PROX1) gene, the function of which was validated previously in a mouse model., Conclusion: Our powerful strategic analysis enabled the discovery of a novel candidate gene, PROX1, associated with WC in an Asian population., (Copyright © 2012 The Obesity Society.)

Background: Meiotic recombination causes a shuffling of homologous chromosomes as they are passed from parents to children. Finding the genomic locations where these crossovers occur is important for genetic association studies, understanding population genetic variation, and predicting disease-causing structural rearrangements. There have been several reports that recombination hotspot usage differs between human populations. But while fine-scale genetic maps exist for European and African populations, none have been constructed for Asians., Results: Here we present the first Asian genetic map with resolution high enough to reveal hotspot usage. We constructed this map by applying a hidden Markov model to genotype data for over 500,000 single nucleotide polymorphism markers from Korean and Mongolian pedigrees which include 980 meioses. We identified 32,922 crossovers with a precision rate of 99%, 97% sensitivity, and a median resolution of 105,949 bp. For direct comparison of genetic maps between ethnic groups, we also constructed a map for CEPH families using identical methods. We found high levels of concordance with known hotspots, with approximately 72% of recombination occurring in these regions. We investigated the hypothesized contribution of recombination problems to age-related aneuploidy. Our large sample size allowed us to detect a weak but significant negative effect of maternal age on recombination rate., Conclusions: We have constructed the first fine-scale Asian genetic map. This fills an important gap in the understanding of recombination pattern variation and will be a valuable resource for future research in population genetics. Our map will improve the accuracy of linkage studies and inform the design of genome-wide association studies in the Asian population.

The estimated glomerular filtration rate is a well-known measure of renal function and is widely used to follow the course of disease. Although there have been several investigations establishing the genetic background contributing to renal function, Asian populations have rarely been used in these genome-wide studies. Here, we aimed to find candidate genetic determinants of renal function in 1007 individuals from 73 extended families of Mongolian origin. Linkage analysis found two suggestive regions near 9q21 (logarithm of odds (LOD) 2.82) and 15q15 (LOD 2.70). The subsequent family-based association study found 2 and 10 significant single-nucleotide polymorphisms (SNPs) in each region, respectively. The strongest SNPs on chromosome 9 and 15 were rs17400257 and rs1153831 with P-values of 7.21 × 10(-9) and 2.47 × 10(-11), respectively. Genes located near these SNPs are considered candidates for determining renal function and include FRMD3, GATM, and SPATA5L1. Thus, we identified possible loci that determine renal function in an isolated Asian population. Consistent with previous reports, our study found genes linked and associated with renal function in other populations.

Background: Musical abilities such as recognising music and singing performance serve as means for communication and are instruments in sexual selection. Specific regions of the brain have been found to be activated by musical stimuli, but these have rarely been extended to the discovery of genes and molecules associated with musical ability., Methods: A total of 1008 individuals from 73 families were enrolled and a pitch-production accuracy test was applied to determine musical ability. To identify genetic loci and variants that contribute to musical ability, we conducted family-based linkage and association analyses, and incorporated the results with data from exome sequencing and array comparative genomic hybridisation analyses., Results: We found significant evidence of linkage at 4q23 with the nearest marker D4S2986 (LOD=3.1), whose supporting interval overlaps a previous study in Finnish families, and identified an intergenic single nucleotide polymorphism (SNP) (rs1251078, p = 8.4 × 10(-17)) near UGT8, a gene highly expressed in the central nervous system and known to act in brain organisation. In addition, a non-synonymous SNP in UGT8 was revealed to be highly associated with musical ability (rs4148254, p = 8.0 × 10(-17)), and a 6.2 kb copy number loss near UGT8 showed a plausible association with musical ability (p = 2.9 × 10(-6))., Conclusions: This study provides new insight into the genetics of musical ability, exemplifying a methodology to assign functional significance to synonymous and non-coding alleles by integrating multiple experimental methods.

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.

Objective: Gastric carcinogenesis is a multi-step process and is influenced by several etiological agents, including the host's genetic factors. Since whether a patient remains with chronic superficial gastritis (CSG) or progresses to either chronic atrophic gastritis (CAG) or gastric carcinoma (GC) could be a genetic predisposition unique in each population, we hypothesized that host human leukocyte antigen (HLA) alleles could be discriminative in predicting the risk of CSG progression to precancerous CAG and GC in Koreans., Methods: A total of 165 patients with gastric disorders (CSG, 62; CAG, 69 and GC, 34), were selected to investigate the association of HLA class II alleles with the progression of CSG to CAG or GC. HLA genotypes were obtained by the polymerase chain reaction-sequence based typing method., Results: The phenotypic frequencies of DRB1*1101 and DQA1*0505 were significantly higher in the CAG group compared to those in the CSG group. In the subjects with Helicobacter pylori (H. pypori) (+), the frequencies of DRB1*1501 and DQB1*0602 were significantly lower in the CAG compared to those in the CSG. Further analysis showed that sex (P < 0.05, OR = 0.41-0.42) and age (P < 0.05, OR = 1.05) also affected the risk of progression from CSG to CAG in H. pylori (+) patients carrying the DRB1*1501 or DQB1*0602 allele. Additionally, the frequency of DRB1*0404 in the GC group was significantly higher than that in the gastritis group., Conclusion: Our findings strongly imply an association between HLA class II alleles and the risk of CAG development and GC progression in Koreans.

Recent advances in sequencing technologies have initiated an era of personal genome sequences. To date, human genome sequences have been reported for individuals with ancestry in three distinct geographical regions: a Yoruba African, two individuals of northwest European origin, and a person from China. Here we provide a highly annotated, whole-genome sequence for a Korean individual, known as AK1. The genome of AK1 was determined by an exacting, combined approach that included whole-genome shotgun sequencing (27.8x coverage), targeted bacterial artificial chromosome sequencing, and high-resolution comparative genomic hybridization using custom microarrays featuring more than 24 million probes. Alignment to the NCBI reference, a composite of several ethnic clades, disclosed nearly 3.45 million single nucleotide polymorphisms (SNPs), including 10,162 non-synonymous SNPs, and 170,202 deletion or insertion polymorphisms (indels). SNP and indel densities were strongly correlated genome-wide. Applying very conservative criteria yielded highly reliable copy number variants for clinical considerations. Potential medical phenotypes were annotated for non-synonymous SNPs, coding domain indels, and structural variants. The integration of several human whole-genome sequences derived from several ethnic groups will assist in understanding genetic ancestry, migration patterns and population bottlenecks.