Journal of Human Genetics

Trinh, Joanne; Vilariño-Güell, Carles; Ross, Owen A

doi: 10.1038/jhg.2015.76pmid: 26134513

Vinayagamoorthy, Nadimuthu; Yim, Seon-Hee; Jung, Seung-Hyun; Park, Sung-Won; Kim, Young Jin; Kim, Bong-Jo; Chung, Yeun-Jun

doi: 10.1038/jhg.2015.46pmid: 25972035

Calcium is a universal intracellular messenger that has an important role in controlling various cellular processes. In this study, we explored genetic polymorphisms to identify novel loci influencing serum calcium levels in East Asians through a two-stage genome-wide association study with the sample of 8642 unrelated Koreans (4558 for discovery and 4093 for replication). Using single-nucleotide polymorphism (SNP) arrays, we discovered 963 associated SNPs in stage 1, and replicated 105 SNPs among them in stage 2. We examined them in a combined set of stage 1 and 2 samples and observed that 65 SNPs were significantly associated with serum calcium levels. Among them, rs13068893 in the CASR gene showed the strongest significance (P=3.85 × 10−8). Considering the high allele frequency and significance level of the rs13068893C>G in the CASR gene, this SNP may have a key role in regulating the serum calcium level. We also successfully replicated the four loci (CASR, CSTA, DGKD and GCKR) using our data set that have been previously reported to be significantly associated with calcium levels in Europeans and Indians. Further studies with more East Asian subjects or meta-analyses on them may enable validation of our results and identification of novel genetic loci associated with serum calcium levels.

Suvichapanich, Supharat; Jittikoon, Jiraphun; Wichukchinda, Nuanjun; Kamchaisatian, Wasu; Visudtibhan, Anannit; Benjapopitak, Suwat; Nakornchai, Somjai; Manuyakorn, Wiparat; Mahasirimongkol, Surakameth

doi: 10.1038/jhg.2015.47pmid:

Stange, Katja; Ott, Claus-Eric; Schmidt-von Kegler, Mareen; Gillesen-Kaesbach, Gabriele; Mundlos, Stefan; Dathe, Katarina; Seemann, Petra

doi: 10.1038/jhg.2015.48pmid: 25994865

We report on a Brachydactyly Type C (BDC) patient with clinically inconspicuous parents. Molecular genetic analyses revealed compound heterozygosity for two GDF5 variants. The variant c.956G>T (p.Gly319Val) was inherited from her mother and has been reported in exome sequencing projects, whereas c.1073T>C (p.Ile358Thr) has never been reported so far. In silico, both variants were predicted to be ‘disease-causing’, but the fact that p.Ile358Thr was predicted by SIFT to be ‘tolerated’ raised our suspicion. Therefore, we performed in vitro assays. To our surprise, GDF5G319V showed pronounced loss of function in luciferase reporter assays and in vitro chondrogenesis, whereas GDF5I358T and GDF5WT had comparable biological activities. Western blot analyses revealed decreased protein levels after overexpression of GDF5G319V. In absence of linkage or de novo mutation, several scenarios could explain the underlying mechanism of the patient’s phenotype. Owing to reduced activity of GDF5G319V in our functional assays, p.Gly319Val might be causative for BDC, but typically evoke an unrecognizably mild phenotype or even nonpenetrance. Another possibility is that our assays failed to pinpoint the disease-causing mechanism of the p.Ile358Thr allele. A final possibility is that compound heterozygosity for p.Ile358Thr and p.Gly319Val is more deleterious to GDF5 activity than either variant alone. Until all possible explanations can be rigorously tested experimentally, a precise recurrence risk counseling for the parents and the affected child is not possible.

Li, Miao; Liu, Bailing; Li, Lu; Zhang, Chen; Zhou, Qi

doi: 10.1038/jhg.2015.42pmid: 26016409

Although the connection between SEPS1 gene variants and Hashimoto’s thyroiditis (HT) has been established in Europeans, the relationship between the SEPS1 gene and HT remains unclear in Han Chinese. Here we aimed to investigate the potential association between SEPS1 variants and HT in the Han population. In addition, the effects of SEPS1 haplotypes on the susceptibility of the development of immune-mediated diseases with an inflammatory component will also be evaluated. Seven single-nucleotide polymorphisms (SNPs) with minor allele frequency ⩾0.05 were genotyped in 1013 HT patients and 2998 healthy controls from genetically independent Han Chinese individuals. We identified that the rs28665122 SNP was significantly associated with HT, both in the female group (allelic P=0.002644 and genotypic P=0.010326) and the combined data set (allelic P=0.000518 and genotypic P=0.002731). Further analyses based on haplotypes indicated that a two-SNP haplotype (rs2009895–rs28665122) was significantly associated with HT (global P=0.0036), which was also observed in females (global P=0.0162) but not in males. Our findings provide further supporting evidence that confirms the results of previous studies, which suggested potential roles of the SEPS1 gene in the pathogenesis and etiology of HT.

Guo, Ruolan; Zhu, Guosheng; Zhu, Huimin; Ma, Ruiyu; Peng, Ying; Liang, Desheng; Wu, Lingqian

doi: 10.1038/jhg.2015.43pmid: 25972034

Dystrophinopathy is a group of inherited diseases caused by mutations in the DMD gene. Within the dystrophinopathy spectrum, Duchenne and Becker muscular dystrophies are common X-linked recessive disorders that mainly feature striated muscle necrosis. We combined multiplex ligation-dependent probe amplification with Sanger sequencing to detect large deletions/duplications and point mutations in the DMD gene in 613 Chinese patients. A total of 571 (93.1%) patients were diagnosed, including 428 (69.8%) with large deletions/duplications and 143 (23.3%) with point mutations. Deletion/duplication breakpoints gathered mostly in introns 44–55. Reading frame rules could explain 88.6% of deletion mutations. We identified seventy novel point mutations that had not been previously reported. Spectrum expansion and genotype–phenotype analysis of DMD mutations on such a large sample size in Han Chinese population would provide new insights into the pathogenic mechanism underlying dystrophinopathies.

Kumar, Amrendra; Das, Sudipta; Agrawal, Anurag; Mukhopadhyay, Indranil; Ghosh, Balaram

doi: 10.1038/jhg.2015.45pmid: 25994869

Asthma is a complex, multifactorial disease resulting due to dysregulated immune responses. Genetic factors contribute significantly to asthma pathogenesis, and identification of these factors is one of the major goals in understanding the disease. Th1/Th2 helper differentiation has a critical role in modulating the phenotypes associated with atopic asthma. This study was aimed at identifying genetic modifiers of asthma in selected genes involved in T helper differentiation. A total of 354 single-nucleotide polymorphisms (SNPs) in 33 candidate genes were genotyped in a case–control cohort (cases=147, controls=199) and families (n=247) using Illumina’s Golden Gate Assay. Five SNPs, rs3733475A/C (IRF2), rs2069832A/G (IL6), rs2012075G/A (IFNGR2) and rs1400656G/A (STAT4) and rs1805011C/A (IL4RA) were found to be associated with asthma in family based as well as in case–control analyses (P=0.002, P=0.001, P=0.004, P=0.003 and P=0.001, respectively). Interestingly, the minor alleles at these loci showed a protective effect. A five loci haplotype, TAACG, in IRF2 gene, was significantly associated with asthma in families (P=1.1 × 10−6) and in case–control cohort (P=0.01). In conclusion, our studies led to identification of some key candidate genes, namely IRF2, IL6, IFNGR2, STAT4 and IL4RA that modulate genetic susceptibility to asthma in the Indian population. Also, this is the first report of independent association of IL6 gene polymorphism with atopic asthma.

Mitsunaga, Shigeki; Hosomichi, Kazuyoshi; Okudaira, Yuko; Nakaoka, Hirofumi; Suzuki, Yasuo; Kuwana, Masataka; Sato, Shinji; Kaneko, Yuko; Homma, Yasuhiko; Oka, Akira; Shiina, Takashi; Inoko, Hidetoshi; Inoue, Ituro

Kim, Bo-Hye; Kim, Han-Na; Roh, Seung-Ju; Lee, Mi Kyeong; Yang, Sarah; Lee, Seung Ku; Sung, Yeon-Ah; Chung, Hye Won; Cho, Nam H; Shin, Chol; Sung, Joohon; Kim, Hyung-Lae

doi: 10.1038/jhg.2015.52pmid:

Gan-Or, Ziv

doi: 10.1038/jhg.2015.73pmid: 26108144