In a sixteen year follow-up study in Framingham, it was found that diabetics in general show an increased morbidity and mortality from all cardiovascular causes. Insulin-treated diabetic women showed the greatest relative mortality from coronary heart disease. Diabetics were found to have higher lipid values, more hypertension and more obesity, even prior to diagnosis. When all the associated risk factors, individually or together, were taken into consideration their presence could not entirely explain the increase in cardiovascular morbidity and mortality experienced by the diabetic. An as yet unknown factor appears to be present in diabetics that could be responsible for much of the higher incidence of cardiovascular complications in diabetics.

To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P=5.4×10−60) and 9q31.2 (P=2.2×10−33), we identified 30 novel menarche loci (all P<5×10−8) and found suggestive evidence for a further 10 loci (P<1.9×10−6). New loci included four previously associated with BMI (in/near FTO, SEC16B, TRA2B and TMEM18), three in/near other genes implicated in energy homeostasis (BSX, CRTC1, and MCHR2), and three in/near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and MAGENTA pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.

We conducted a meta-analysis of genome-wide association data to detect genes influencing age at menarche in 17,510 women. The strongest signal was at 9q31.2 (P = 1.7 × 10 −9 ), where the nearest genes include TMEM38B, FKTN, FSD1L, TAL2 and ZNF462. The next best signal was near the LIN28B gene (rs7759938; P = 7.0 × 10 −9 ), which also influences adult height. We provide the first evidence for common genetic variants influencing female sexual maturation.Menarche is the start of menstruation and occurs at a mean age of approximately 13 years, normally about 2 years after the onset of puberty 1 . Twin and family studies suggest a significant genetic component to menarcheal age, with at least 50% heritability 2-4 . Linkage and candidate gene studies have not confirmed any loci that influence normal variation in age at menarche 4,5 . Genome-wide association (GWA) studies have been successful in identifying many variants associated with complex disease and quantitative traits and we therefore used this approach to identify genes involved in determining age at menarche. As earlier age at menarche is associated with shorter stature and obesity, the identified variants may not only clarify the genetic control of female sexual maturation but may also point to regulatory mechanisms involved in normal human growth and obesity.We carried out a meta-analysis of 17,510 females from eight different population-based cohorts: Age/Gene Environment Susceptibility-Reykjavik Study (AGES-Reykjavik), Atherosclerosis Risk in Communities (ARIC) Study, Framingham Heart Study (FHS), Amish HAPI Heart Study, InCHIANTI Study, Rotterdam Study I and II and TWINS UK Study (Supplementary Note online). Women of European descent, with self-reported age at menarche between 9 and 17 years (representing the 1st to 99th percentile, with mean age at menarche of 13.12 (s.d. 1.5) years), were included. Agreement between adult-recalled and prospectively collected age at menarche is reported to be good (κ statistic = 0.81) 6 . Each study conducted a GWA analysis using linear regression or linear mixed-effects models with an additive genetic model adjusting for birth year or birth cohort (FHS), with additional adjustments for population structure when appropriate. Approximately 2.55 million autosomal SNPs, imputed with reference to the HapMap CEU panel, passed quality control criteria. We then conducted a metaanalysis using a fixed-effects model based on inverse variance weighting. Full details of cohorts and methods are given in Supplementary Table 1 and Supplementary Methods online.Twenty-eight SNPs passed the conventional genome-wide significance threshold of P < 5 × 10 −8 and were at either 9q31.2 or 6q21 (Supplementary Table 2 and Supplementary Fig. 1 online). The 18 SNPs on chromosome 9 were in linkage disequilibrium (LD), with r 2 > 0.31, as were the 10 SNPs on chromosome 6, with r 2 > 0.96 ( Fig. 1 and Supplementary Table 2). To identify more than one signal that could account for the association findings, we carried out conditional analysis ...

Circulating levels of inflammatory markers can predict cardiovascular disease risk. To identify genes influencing the levels of these markers, we genotyped 1,343 single-nucleotide polymorphisms (SNPs) in 1,184 African Americans from the Health, Aging and Body Composition (Health ABC) Study. Using admixture mapping, we found a significant association of interleukin 6 soluble receptor (IL-6 SR) with European ancestry on chromosome 1 (LOD 4.59), in a region that includes the gene for this receptor (IL-6R). Genotyping 19 SNPs showed that the effect is largely explained by an allele at 4% frequency in West Africans and at 35% frequency in European Americans, first described as associated with IL-6 SR in a Japanese cohort. We replicate this association (P<<1.0x10-12) and also demonstrate a new association with circulating levels of a different molecule, IL-6 (P<3.4x10-5). After replication in 1,674 European Americans from Health ABC, the combined result is even more significant: P<<1.0x10-12 for IL-6 SR, and P<2.0x10-9 for IL-6. These results also serve as an important proof of principle, showing that admixture mapping can not only coarsely localize but can also fine map a phenotypically important variant.