Gitte Andersen

Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes

Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and ∼2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 × 10−14), CDC123-CAMK1D (P = 1.2 × 10−10), TSPAN8-LGR5 (P = 1.1 × 10−9), THADA (P = 1.1 × 10−9), ADAMTS9 (P = 1.2 × 10−8) and NOTCH2 (P = 4.1 × 10−8) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.

Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity

Obesity results from the interaction of genetic and environmental factors. To search for sequence variants that affect variation in two common measures of obesity, weight and body mass index (BMI), both of which are highly heritable, we performed a genome-wide association (GWA) study with 305,846 SNPs typed in 25,344 Icelandic, 2,998 Dutch, 1,890 European Americans and 1,160 African American subjects and combined the results with previously published results from the Diabetes Genetics Initiative (DGI) on 3,024 Scandinavians. We selected 43 variants in 19 regions for follow-up in 5,586 Danish individuals and compared the results to a genome-wide study on obesity-related traits from the GIANT consortium. In total, 29 variants, some correlated, in 11 chromosomal regions reached a genome-wide significance threshold of P < 1.6 × 10−7. This includes previously identified variants close to or in the FTO, MC4R, BDNF and SH2B1 genes, in addition to variants at seven loci not previously connected with obesity.

A variant in CDKAL1 influences insulin response and risk of type 2 diabetes.

We conducted a genome-wide association study for type 2 diabetes (T2D) in Icelandic cases and controls, and we found that a previously described variant in the transcription factor 7-like 2 gene (TCF7L2) gene conferred the most significant risk. In addition to confirming two recently identified risk variants, we identified a variant in the CDKAL1 gene that was associated with T2D in individuals of European ancestry (allele-specific odds ratio (OR) = 1.20 (95% confidence interval, 1.13–1.27), P = 7.7 × 10−9) and individuals from Hong Kong of Han Chinese ancestry (OR = 1.25 (1.11–1.40), P = 0.00018). The genotype OR of this variant suggested that the effect was substantially stronger in homozygous carriers than in heterozygous carriers. The ORs for homozygotes were 1.50 (1.31–1.72) and 1.55 (1.23–1.95) in the European and Hong Kong groups, respectively. The insulin response for homozygotes was approximately 20% lower than for heterozygotes or noncarriers, suggesting that this variant confers risk of T2D through reduced insulin secretion.

Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes

We performed a genome-wide association scan to search for sequence variants conferring risk of prostate cancer using 1,501 Icelandic men with prostate cancer and 11,290 controls. Follow-up studies involving three additional case-control groups replicated an association of two variants on chromosome 17 with the disease. These two variants, 33 Mb apart, fall within a region previously implicated by family-based linkage studies on prostate cancer. The risks conferred by these variants are moderate individually (allele odds ratio of about 1.20), but because they are common, their joint population attributable risk is substantial. One of the variants is in TCF2 (HNF1β), a gene known to be mutated in individuals with maturity-onset diabetes of the young type 5. Results from eight case-control groups, including one West African and one Chinese, demonstrate that this variant confers protection against type 2 diabetes.

The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm

Recently, two common sequence variants on 9p21, tagged by rs10757278-G and rs10811661-T, were reported to be associated with coronary artery disease (CAD) and type 2 diabetes (T2D), respectively. We proceeded to further investigate the contributions of these variants to arterial diseases and T2D. Here we report that rs10757278-G is associated with, in addition to CAD, abdominal aortic aneurysm (AAA; odds ratio (OR) = 1.31, P = 1.2 × 10−12) and intracranial aneurysm (OR = 1.29, P = 2.5 × 10−6), but not with T2D. This variant is the first to be described that affects the risk of AAA and intracranial aneurysm in many populations. The association of rs10811661-T to T2D replicates in our samples, but the variant does not associate with any of the five arterial diseases examined. These findings extend our insight into the role of the sequence variant tagged by rs10757278-G and show that it is not confined to atherosclerotic diseases.

SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations

We conducted a genome-wide association study using 207,097 SNP markers in Japanese individuals with type 2 diabetes and unrelated controls, and identified KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) to be a strong candidate for conferring susceptibility to type 2 diabetes. We detected consistent association of a SNP in KCNQ1 (rs2283228) with the disease in several independent case-control studies (additive model P = 3.1 × 10−12; OR = 1.26, 95% CI = 1.18–1.34). Several other SNPs in the same linkage disequilibrium (LD) block were strongly associated with type 2 diabetes (additive model: rs2237895, P = 7.3 × 10−9; OR = 1.32, 95% CI = 1.20–1.45, rs2237897, P = 6.8 × 10−13; OR = 1.41, 95% CI = 1.29–1.55). The association of these SNPs with type 2 diabetes was replicated in samples from Singaporean (additive model: rs2237895, P = 8.5 × 10−3; OR = 1.14, rs2237897, P = 2.4 × 10−4; OR = 1.22) and Danish populations (additive model: rs2237895, P = 3.7 × 10−11; OR = 1.24, rs2237897, P = 1.2 × 10−4; OR = 1.36).

Many sequence variants affecting diversity of adult human height

Adult human height is one of the classical complex human traits. We searched for sequence variants that affect height by scanning the genomes of 25,174 Icelanders, 2,876 Dutch, 1,770 European Americans and 1,148 African Americans. We then combined these results with previously published results from the Diabetes Genetics Initiative on 3,024 Scandinavians and tested a selected subset of SNPs in 5,517 Danes. We identified 27 regions of the genome with one or more sequence variants showing significant association with height. The estimated effects per allele of these variants ranged between 0.3 and 0.6 cm and, taken together, they explain around 3.7% of the population variation in height. The genes neighboring the identified loci cluster in biological processes related to skeletal development and mitosis. Association to three previously reported loci are replicated in our analyses, and the strongest association was with SNPs in the ZBTB38 gene.

Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution

We recently described an association between risk of type 2diabetes and variants in the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4), with a population attributable risk (PAR) of 17%–28% in three populations of European ancestry. Here, we refine the definition of the TCF7L2 type 2diabetes risk variant, HapBT2D, to the ancestral T allele of a SNP, rs7903146, through replication in West African and Danish type 2 diabetes case-control studies and an expanded Icelandic study. We also identify another variant of the same gene, HapA, that shows evidence of positive selection in East Asian, European and West African populations. Notably, HapA shows a suggestive association with body mass index and altered concentrations of the hunger-satiety hormones ghrelin and leptin in males, indicating that the selective advantage of HapA may have been mediated through effects on energy metabolism.

Low Physical Activity Accentuates the Effect of the FTO rs9939609 Polymorphism on Body Fat Accumulation

OBJECTIVE—Three independent studies have shown that variation in the fat mass and obesity-associated (FTO) gene associates with BMI and obesity. In the present study, the effect of FTO variation on metabolic traits including obesity, type 2 diabetes, and related quantitative phenotypes was examined. RESEARCH DESIGN AND METHODS—The FTO rs9939609 polymorphism was genotyped in a total of 17,508 Danes from five different study groups. RESULTS—In studies of 3,856 type 2 diabetic case subjects and 4,861 normal glucose-tolerant control subjects, the minor A-allele of rs9939609 associated with type 2 diabetes (odds ratio 1.13 [95% CI 1.06–1.20], P = 9 × 10−5). This association was abolished when adjusting for BMI (1.06 [0.97–1.16], P = 0.2). Among 17,162 middle-aged Danes, the A-allele associated with overweight (1.19 [1.13–1.24], P = 1 × 10−12) and obesity (1.27 [1.20–1.34], P = 2 × 10−16). Furthermore, obesity-related quantitative traits such as body weight, waist circumference, fat mass, and fasting serum leptin levels were significantly elevated in A-allele carriers. An interaction between the FTO rs9939609 genotype and physical activity (P = 0.007) was found, where physically inactive homozygous risk A-allele carriers had a 1.95 ± 0.3 kg/m2 increase in BMI compared with homozygous T-allele carriers. CONCLUSIONS—We validate that variation in FTO is associated with type 2 diabetes when not adjusted for BMI and with an overall increase in body fat mass. Furthermore, low physical activity seems to accentuate the effect of FTO rs9939609 on body fat accumulation.

Mutation analysis of peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) and relationships of identified amino acid polymorphisms to Type II diabetes mellitus

Abstract.Aim/hypothesis: This study aimed to investigate if variability in the peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) gene is associated with Type II (non-insulin-dependent) diabetes mellitus. Methods: The PGC-1 gene was examined in 53 Type II diabetic patients applying single strand conformational polymorphism analysis followed by nucleotide sequencing. Identified variants were genotyped in an association study comprising 483 Type II diabetic patients and 216 glucose-tolerant control subjects. A replication study was done in an additional 201 Type II diabetic patients and 293 glucose-tolerant subjects. Furthermore, a potential interaction between the Pro12Ala polymorphism of PPAR-γ2 and the PGC-1 Gly482Ser variant on risk of Type II diabetes was investigated. Results: A total of seven variants (Ser74Leu, IVS2 + 52C→A, Thr394Thr, Asp475Asp, Gly482Ser, Thr528Thr, and Thr612Met) were identified and investigated in an association study. Six of the variants showed no association with Type II diabetes in the initial study. However, the Gly482Ser polymorphism, was more frequent among Type II diabetic patients (37.0 %) than among glucose-tolerant subjects (30.8 %) (p = 0.032). In a replication study the difference in allele frequencies of the Gly482Ser variant remained significant (p = 0.0135). The combined study yielded an allele frequency of 37.3 % (34.7–39.9) for Type II diabetic patients and 30.5 % (27.7–33.4) for glucose-tolerant subjects (p = 0.0007). No interaction between this variant and the Pro12Ala polymorphism of PPAR-γ2 was observed. Conclusion/interpretation: A widespread Gly482Ser polymorphism of PGC-1 is associated with a 1.34 genotype relative risk of Type II diabetes. [Diabetologia (2001) 44: 2220–2226]