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1.  Mendelian Randomization Studies do not Support a Role for Raised Circulating Triglyceride Levels influencing Type 2 Diabetes, Glucose Levels, or Insulin Resistance 
Diabetes  2011;60(3):1008-1018.
Objective
The causal nature of associations between circulating triglycerides, insulin resistance and type 2 diabetes is unclear. We aimed to use Mendelian randomization to test the hypothesis that raised circulating triglyceride levels causally influence the risk of type 2 diabetes, raised normal fasting glucose levels, and hepatic insulin resistance.
Research design and methods
We tested 10 common genetic variants robustly associated with circulating triglyceride levels against type 2 diabetes status in 5637 cases, 6860 controls, and four continuous outcomes (reflecting glycemia and hepatic insulin resistance) in 8271 non-diabetic individuals from four studies.
Results
Individuals carrying greater numbers of triglyceride-raising alleles had increased circulating triglyceride levels (0.59 SD [95% CI: 0.52, 0.65] difference between the 20% of individuals with the most alleles and the 20% with the fewest alleles). There was no evidence that carriers of greater numbers of triglyceride-raising alleles were at increased risk of type 2 diabetes (per weighted allele odds ratio (OR) 0.99 [95% CI: 0.97, 1.01]; P = 0.26). In non-diabetic individuals, there was no evidence that carriers of greater numbers of triglyceride-raising alleles had increased fasting insulin levels (0.00 SD per weighted allele [95% CI: −0.01, 0.02]; P = 0.72) or increased fasting glucose levels (0.00 SD per weighted allele [95% CI: −0.01, 0.01]; P = 0.88). Instrumental variable analyses confirmed that genetically raised circulating triglyceride levels were not associated with increased diabetes risk, fasting glucose or fasting insulin, and, for diabetes, showed a trend towards a protective association (OR per 1 SD increase in log10-triglycerides: 0.61 [95% CI: 0.45, 0.83]; P = 0.002).
Conclusion
Genetically raised circulating triglyceride levels do not increase the risk of type 2 diabetes, or raise fasting glucose or fasting insulin levels in non-diabetic individuals. One explanation for our results is that raised circulating triglycerides are predominantly secondary to the diabetes disease process rather than causal.
doi:10.2337/db10-1317
PMCID: PMC3046819  PMID: 21282362
2.  Common variants in WFS1 confer risk of type 2 diabetes 
Nature genetics  2007;39(8):951-953.
We studied genes involved in pancreatic β cell function and survival, identifying associations between SNPs in WFS1 and diabetes risk in UK populations that we replicated in an Ashkenazi population and in additional UK studies. In a pooled analysis comprising 9,533 cases and 11,389 controls, SNPs in WFS1 were strongly associated with diabetes risk. Rare mutations in WFS1 cause Wolfram syndrome; using a gene-centric approach, we show that variation in WFS1 also predisposes to common type 2 diabetes.
doi:10.1038/ng2067
PMCID: PMC2672152  PMID: 17603484
3.  A common variant of HMGA2 is associated with adult and childhood height in the general population 
Nature genetics  2007;39(10):1245-1250.
Human height is a classic, highly heritable quantitative trait. To begin to identify genetic variants influencing height, we examined genome-wide association data from 4,921 individuals. Common variants in the HMGA2 oncogene, exemplified by rs1042725, were associated with height (P = 4 × 10−8). HMGA2 is also a strong biological candidate for height, as rare, severe mutations in this gene alter body size in mice and humans, so we tested rs1042725 in additional samples. We confirmed the association in 19,064 adults from four further studies (P = 3 × 10−11, overall P = 4 × 10−16, including the genome-wide association data). We also observed the association in children (P = 1 × 10−6, N = 6,827) and a tall/short case-control study (P = 4 × 10−6, N = 3,207). We estimate that rs1042725 explains ~0.3% of population variation in height (~0.4 cm increased adult height per C allele). There are few examples of common genetic variants reproducibly associated with human quantitative traits; these results represent, to our knowledge, the first consistently replicated association with adult and childhood height.
doi:10.1038/ng2121
PMCID: PMC3086278  PMID: 17767157
4.  Linkage disequilibrium mapping of the replicated type 2 diabetes linkage signal on chromosome 1q 
Diabetes  2009;58(7):1704-1709.
Objective
Linkage of the chromosome 1q21-25 region to type 2 diabetes has been demonstrated in multiple ethnic groups. We performed common variant fine-mapping across a 23Mb interval in a multiethnic sample to search for variants responsible for this linkage signal.
Research Design and Methods
In all, 5,290 SNPs were successfully genotyped in 3,179 T2D cases and controls from eight populations with evidence of 1q linkage. Samples were ascertained using strategies designed to enhance power to detect variants causal for 1q-linkage. Following imputation, we estimate ~80% coverage of common variation across the region (r2>0.8, Europeans). Association signals of interest were evaluated through in silico replication and de novo genotyping in approximately 8,500 cases and 12,400 controls.
Results
Association mapping of the 23Mb region identified two strong signals, both restricted to the subset of European-descent samples. The first mapped to the NOS1AP (CAPON) gene region (lead SNP: rs7538490, OR 1.38 (95% CI, 1.21-1.57), p=1.4×10-6 in 999 cases and 1,190 controls): the second within an extensive region of linkage disequilibrium that includes the ASH1L and PKLR genes (lead SNP: rs11264371, OR 1.48 [1.18-1.76], p=1.0×10-5, under a dominant model). However, there was no evidence for association at either signal on replication, and, across all data (>24,000 subjects), no indication that these variants were causally-related to T2D status.
Conclusion
Detailed fine-mapping of the 23Mb region of replicated linkage has failed to identify common variant signals contributing to the observed signal. Future studies should focus on identification of causal alleles of lower frequency and higher penetrance.
doi:10.2337/db09-0081
PMCID: PMC2699860  PMID: 19389826
chromosome 1q; linkage; association
5.  Genome-wide association analysis identifies 20 loci that influence adult height 
Nature genetics  2008;40(5):575-583.
Adult height is a model polygenic trait, but there has been limited success in identifying the genes underlying its normal variation. To identify genetic variants influencing adult human height, we used genome-wide association data from 13,665 individuals and genotyped 39 variants in an additional 16,482 samples. We identified 20 variants associated with adult height (P < 5 × 10−7, with 10 reaching P < 1 × 10−10). Combined, the 20 SNPs explain ~3% of height variation, with a ~5 cm difference between the 6.2% of people with 17 or fewer ‘tall’ alleles compared to the 5.5% with 27 or more ‘tall’ alleles. The loci we identified implicate genes in Hedgehog signaling (IHH, HHIP, PTCH1), extracellular matrix (EFEMP1, ADAMTSL3, ACAN) and cancer (CDK6, HMGA2, DLEU7) pathways, and provide new insights into human growth and developmental processes. Finally, our results provide insights into the genetic architecture of a classic quantitative trait.
doi:10.1038/ng.121
PMCID: PMC2681221  PMID: 18391952

Results 1-5 (5)