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Studies Uncover Variants Influencing BMI in East Asian Populations

NEW YORK (GenomeWeb News) – Some of the same loci that influence body mass index in Europeans also contribute to BMI in East Asians, though other BMI-associated sites seem to have population-specific effects, according to a pair of studies published online yesterday in Nature Genetics.

An international team led by investigators at Riken found two new BMI-linked loci — a chromosome 6 site in the CDKAL1 gene and a chromosome 9 locus in the promoter of a gene called KLF9 — through genome-wide association and replication studies involving tens of thousands of individuals from Japan and other parts of East Asia. Those analyses also identified five of the same loci found through past GWAS in European and other populations.

A few dozen loci have been implicated in BMI, Riken researcher Toshihiro Tanaka, senior author on the new GWAS, and colleagues explained. Even so, the majority of genetic studies done on this obesity-related trait so far have focused on European populations.

"The degree of adiposity and the risks of diseases exacerbated by obesity are greater in Asians than in Europeans when evaluated with the same BMI," the study authors explained. "Thus, the study of Asian populations might lead to the identification of new obesity-associated loci and provide insight into the genetic architecture of obesity."

In an effort to get a more complete picture of the genetic factors influencing BMI both across populations and within the East Asian population, Tanaka and colleagues first looked at more than two million directly genotyped or imputed SNPs in the genomes of 26,620 Japanese individuals enrolled through the BioBank Japan Project.

That analysis unearthed three sites with genome-wide significant associations to BMI: two known BMI-related loci on chromosomes 11 and 19, near the BDNF and GIPR genes, respectively, and a new chromosome 9 locus falling in the KLF9 gene promoter.

They then did a series of replication analyses on the most promising SNPs from the discovery set, using data on individuals from two more BioBank Japan cohorts and a third cohort representing almost 28,000 East Asian individuals. Members of the third cohort were also assessed for a meta-analysis published in Nature Genetics online yesterday by some members of the same research team.

Seven loci remained associated with BMI following the GWAS discovery and replication analyses.

In addition to the three significantly associated loci found in the initial Japanese GWAS, researchers detected another new locus within CDKAL1, a chromosome 6 gene previously implicated in type 2 diabetes. Two more new loci seemed to correspond somewhat with BMI but did not show statistically significant associations. They also tracked down three more BMI-related sites known from past GWAS efforts.

The team's between-population comparisons for the nine new, known, or suspected loci indicated that variants at each site had the same sorts of directional effects in European populations as they did in the East Asians.

But researchers did not see links between the KLF9 locus and BMI in the Europeans, suggesting this site may have population-specific effects on BMI. Likewise, when they looked at loci implicated in BMI in studies of Europeans and Koreans, investigators saw similar effects for some but not all of the variants.

At least one variant at the KLF9 site showed genetic interactions with a SNP in the MSTN gene on chromosome 2, researchers reported, though the latter locus was not significantly associated with BMI itself.

Adding to these findings, a meta-analysis of eight East Asian cohorts representing 27,715 individuals — combined with in silico and de novo replication analyses on tens of thousands more individuals from East Asia — uncovered two more new BMI-associated sites in and around the PCSK1 and GP2 genes.

Members of that research team also saw ties between BMI and the CDKAL1 locus identified in the Asian BMI GWAS. They also verified associations for 10 sites reported in previous GWAS, though they did not see BMI-related associations at the KLF9 locus described in the East Asian BMI study.

For the first stage of that study, researchers looked at some 2.4 million directly genotyped or imputed SNPs in 27,715 East Asians enrolled through eight past studies.

Nearly 850 SNPs were carried forward from that analysis to subsequent in silico testing in 37,691 individuals from seven more cohorts. In a second replication step, the team relied on de novo genotype information for another 17,642 East Asians from three additional studies.

Overall, that group identified 10 loci with genome-wide significant ties to BMI in the East Asian populations, including three sites not known from previous European studies. Three more suggestive associations popped out of their analyses but did not reach this level of significance. Again, variants near the type 2 diabetes associated gene CDKAL1 turned up amongst the newly associated loci.

"Findings from this study may shed light on new pathways involved in obesity and demonstrate the value of conducting genetic studies in non-European populations," Vanderbilt University researcher Xiao-Ou Shu, co-senior author on the meta-analysis, and colleagues wrote.

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