Identifying Highly Conserved and Highly Differentiated Gene Ontology Categories in Human Populations

Detecting and interpreting certain system-level characteristics associated with human population genetic differences is a challenge for human geneticists. In this study, we conducted a population genetic study using the HapMap genotype data to identify certain special Gene Ontology (GO) categories associated with high/low genetic difference among 11 Hapmap populations. Initially, the genetic differences in each gene region among these populations were measured using allele frequency, linkage disequilibrium (LD) pattern, and transferability of tagSNPs. The associations between each GO term and these genetic differences were then identified. The results showed that cellular process, catalytic activity, binding, and some of their sub-terms were associated with high levels of genetic difference, and genes involved in these functional categories displayed, on average, high genetic diversity among different populations. By contrast, multicellular organismal processes, molecular transducer activity, and some of their sub-terms were associated with low levels of genetic difference. In particular, the neurological system process under the multicellular organismal process category had low levels of genetic difference; the neurological function also showed high evolutionary conservation between species in some previous studies. These results may provide a new insight into the understanding of human evolutionary history at the system-level

Association of genetic variation in FTO with risk of obesity and type 2 diabetes with data from 96,551 East and South Asians

Aims/hypothesis: $FTO$ harbours the strongest known obesity-susceptibility locus in Europeans. While there is growing evidence for a role for $FTO$ in obesity risk in Asians, its association with type 2 diabetes, independently of BMI, remains inconsistent. To test whether there is an association of the $FTO$ locus with obesity and type 2 diabetes, we conducted a meta-analysis of 32 populations including 96,551 East and South Asians. Methods: All studies published on the association between $FTO$-rs9939609 (or proxy [r$^2$ > 0.98]) and BMI, obesity or type 2 diabetes in East or South Asians were invited. Each study group analysed their data according to a standardised analysis plan. Association with type 2 diabetes was also adjusted for BMI. Random-effects meta-analyses were performed to pool all effect sizes. Results: The $FTO$-rs9939609 minor allele increased risk of obesity by 1.25-fold/allele (p = 9.0 × 10$^{−19}$), overweight by 1.13-fold/allele (p = 1.0 × 10$^{−11}$) and type 2 diabetes by 1.15-fold/allele (p = 5.5 × 10$^{−8}$). The association with type 2 diabetes was attenuated after adjustment for BMI (OR 1.10-fold/allele, p = 6.6 × 10$^{−5}$). The $FTO$-rs9939609 minor allele increased BMI by 0.26 kg/m2 per allele (p = 2.8 × 10$^{−17}$), WHR by 0.003/allele (p = 1.2 × 10$^{−6}$), and body fat percentage by 0.31%/allele (p = 0.0005). Associations were similar using dominant models. While the minor allele is less common in East Asians (12–20%) than South Asians (30–33%), the effect of $FTO$ variation on obesity-related traits and type 2 diabetes was similar in the two populations. Conclusions/interpretation: $FTO$ is associated with increased risk of obesity and type 2 diabetes, with effect sizes similar in East and South Asians and similar to those observed in Europeans. Furthermore, $FTO$ is also associated with type 2 diabetes independently of BMI. Electronic supplementary material The online version of this article (doi:10.1007/s00125-011-2370-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users

Comparison of genome-wide variation between Malawians and African ancestry HapMap populations

Understanding genetic variation between populations is important because it affects the portability of human genome wide analytical methods. We compared genetic variation and substructure between Malawians and other African and non-African HapMap populations. Allele frequencies and adjacent linkage disequilibrium (LD) were measured for 617,715 single nucleotide polymorphisms (SNPs) across subject genomes. Allele frequencies in the Malawian population (N = 226) were highly correlated with allele frequencies in HapMap populations of African Ancestry (AFA, N = 376), namely Yoruban in Ibadan, Nigeria (Spearman’s r(2) = 0.97), Luhya in Webuye, Kenya (r(2) = 0.97), African Americans in the southwest United States (r(2) = 0.94), and Maasai in Kinyawa, Kenya (r(2) = 0.91). This correlation was much lower between Malawians and other ancestry populations (r(2) < 0.52). LD correlations between Malawians and HapMap populations were strongest for the populations of African ancestry (AFA r(2) > 0.82, other ancestries r(2) < 0.57). Principal components analyses revealed little population substructure within our Malawi sample but provided clear distinction between Malawians, AFA populations, and two European populations. Five SNPs within the lactase gene (LCT) had substantially different allele frequencies between the Malawi population and Maasai in Kenyawa, Kenya (rs3769013, rs730005, rs3769012, rs2304370; p values < 1×10(−33))

The longitudinal association of common susceptibility variants for type 2 diabetes and obesity with fasting glucose level and BMI

<p>Abstract</p> <p>Background</p> <p>Variation in the effects of genetic variants on physiological traits over time or with age may alter the trajectories of these traits. However, few studies have investigated this possibility for variants associated with type 2 diabetes or obesity, and these show little consensus. We aimed to characterise the possible longitudinal associations of common diabetes-susceptibility variants in the <it>KCNJ11</it>, <it>PPARG</it>, <it>TCF7L2, IGF2BP2, CDKAL1, SLC30A8 </it>and <it>HHEX </it>gene loci, with fasting glucose level; and of an obesity-associated variant in the <it>FTO </it>gene, with body mass index (BMI).</p> <p>Methods</p> <p>The study analysed data from the Busselton Health Study (<it>n </it>= 4,554). Cross-sectional association analyses included family data and used the total association test. Longitudinal association analyses of unrelated participant data (<it>n </it>= 2,864) used linear mixed-effects models.</p> <p>Results</p> <p>In cross-sectional analyses, we observed associations of the T allele at the <it>IGF2BP2 </it>single nucleotide polymorphism (SNP) rs4402960 with raised fasting glucose (<it>p </it>= 0.045), and the A allele at the <it>FTO </it>SNP rs9939609 with raised BMI (<it>p </it>= 0.003). Longitudinal analyses showed no significant associations between SNPs and changes in fasting glucose or BMI in the same individuals, either over mean follow-up times of 18.7 and 21.8 years respectively, or with age during adulthood.</p> <p>Conclusions</p> <p>There was no indication that the effects of common type 2 diabetes variants on fasting glucose varied with age during adulthood or over time.</p