Graves' disease is a common autoimmune disorder characterized by thyroid stimulating hormone receptor autoantibodies (TRAb) and hyperthyroidism. To investigate the genetic architecture of Graves' disease, we conducted a genome-wide association study in 1,536 individuals with Graves' disease (cases) and 1,516 controls. We further evaluated a group of associated SNPs in a second set of 3,994 cases and 3,510 controls. We confirmed four previously reported loci (in the major histocompatibility complex, TSHR, CTLA4 and FCRL3) and identified two new susceptibility loci (the RNASET2-FGFR1OP-CCR6 region at 6q27 (P(combined) = 6.85 × 10(-10) for rs9355610) and an intergenic region at 4p14 (P(combined) = 1.08 × 10(-13) for rs6832151)). These newly associated SNPs were correlated with the expression levels of RNASET2 at 6q27, of CHRNA9 and of a previously uncharacterized gene at 4p14, respectively. Moreover, we identified strong associations of TSHR and major histocompatibility complex class II variants with persistently TRAb-positive Graves' disease.

Graves' disease (GD), characterized by autoantibodies targeting antigens specifically expressed in thyroid tissues causing hyperthyroidism, is triggered by a combination of genetic and environmental factors. However, only a few loci for GD risk were confirmed in the various ethnic groups, and additional genetic determinants have to be detected. In this study, we carried out a three-stage study in 9529 patients with GD and 9984 controls to identify new risk loci for GD and found genome-wide significant associations in the overall populations for five novel susceptibility loci: the GPR174-ITM2A at Xq21.1, C1QTNF6-RAC2 at 22q12.3-13.1, SLAMF6 at 1q23.2, ABO at 9q34.2 and an intergenic region harboring two non-coding RNAs at 14q32.2 and one previous indefinite locus, TG at 8q24.22 (Pcombined < 5 × 10(-8)). The genotypes of corresponding variants at 14q32.2 and 8q24.22 were correlated with the expression levels of C14orf64 and a TG transcript skipping exon 46, respectively. This study increased the number of GD loci with compelling evidence and indicated that non-coding RNAs might be potentially involved in the pathogenesis of GD.

Objectives Haplogroup C2a‐M48 is the predominant paternal lineage of Tungusic‐speaking populations, one of the largest population groups in Siberia. Up until now, the origins and dispersal of Tungusic‐speaking populations have remained unclear. In this study, the demographic history of Tungusic‐speaking populations was explored using the phylogenetic analysis of haplogroup C2a‐M86, the major subbranch of C2a‐M48. Materials and methods In total, 18 newly generated Y chromosome sequences from C2a‐M48 males and 20 previously available Y‐chromosome sequences from this haplogroup were analyzed. A highly revised phylogenetic tree of haplogroup C2a‐M86 with age estimates was reconstructed. Frequencies of this lineage in the literature were collected and a comprehensive analysis of this lineage in 13 022 individuals from 245 populations in Eurasia was performed. Results The distribution map of C2a‐M48 indicated the most probable area of origin and diffusion route of this paternal lineage in North Eurasia. Most C2a‐M86 samples from Tungusic‐speaking populations belonged to the sublineage C2a‐F5484, which emerged about 3300 years ago. We identified six unique sublineages corresponding to the Manchu, Evenks, Evens, Oroqen, and Daurpopulations; these sublineages diverged gradually over the past 1900 years. Notably, we observed a clear north‐south dichotomous structure for sublineages derived from C2a‐F5484, consistent with the internal north‐south divergence of Tungusic languages and ethnic groups. Conclusions We identified the important founding paternal haplogroup, C2a‐F5484, for Tungusic‐speaking populations as well as numerous unique subgroups of this haplogroup. We propose that the timeframe for the divergence of C2a‐F5484 corresponds with the early differentiation of ancestral Tungusic‐speaking populations.

Key Points Question Is thyrotoxic periodic paralysis (TPP) a molecular subtype of Graves disease? Findings In this case-control study in a Chinese Han population, 5 TPP susceptibility loci were identified, including 3 specific loci and 2 loci shared by Graves disease and TPP. The ratio of persistent thyrotropin receptor antibody positivity was higher in TPP than in Graves disease, and TPP could be predicted from Graves disease using TPP-specific loci. Meaning A complete genetic architecture will be helpful to understand the pathophysiology of TPP, and a useful prediction model could prevent the onset of TPP, suggesting TPP as a molecular subtype of Graves disease.

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