Objective

To outline new insights into the genetic etiology of schizophrenia.

Methods

We discuss several commonly held beliefs about the genetic issues in schizophrenia.

Results

The complex genetic nature of the illness poses a challenge for investigators seeking causative genetic mutations. Multiple independent research findings are, however converging to identify a relatively small number of chromosomal locations that appear to contain schizophrenia susceptibility genes. Also, a clinically relevant genetic subtype of schizophrenia (22qDS) has been identified. We are developing a better understanding of how schizophrenia relates to other psychiatric disorders. While investigations into the possible roles of dopaminergic and serotonergic systems continue, other approaches that do not require theories of the mechanism of illness are also being used to identify candidate susceptibility genes.

Conclusions

Research to date suggests that our understanding of the pathophysiology of schizophrenia will soon be fundamentally altered by genetic approaches to this complex disease.

Although experimental studies have suggested that insulin-like growth factor I (IGF-I) and its binding protein IGFBP-3 might have a role in the aetiology of coronary artery disease (CAD), the relevance of circulating IGFs and their binding proteins in the development of CAD in human populations is unclear. We conducted a nested case-control study, with a mean follow-up of six years, within the EPIC-Norfolk cohort to assess the association between circulating levels of IGF-I and IGFBP-3 and risk of CAD in up to 1,013 cases and 2,055 controls matched for age, sex and study enrolment date. After adjustment for cardiovascular risk factors, we found no association between circulating levels of IGF-I or IGFBP-3 and risk of CAD (odds ratio: 0.98 (95% Cl 0.90-1.06) per 1 SD increase in circulating IGF-I; odds ratio: 1.02 (95% Cl 0.94-1.12) for IGFBP-3). We examined associations between tagging single nucleotide polymorphisms (tSNPs) at the IGF1 and IGFBP3 loci and circulating IGF-I and IGFBP-3 levels in up to 1,133 cases and 2,223 controls and identified three tSNPs (rs1520220, rs3730204, rs2132571) that showed independent association with either circulating IGF-I or IGFBP-3 levels. In an assessment of 31 SNPs spanning the IGF1 or IGFBP3 loci, none were associated with risk of CAD in a meta-analysis that included EPIC-Norfolk and eight additional studies comprising up to 9,319 cases and 19,964 controls. Our results indicate that IGF-I and IGFBP-3 are unlikely to be importantly involved in the aetiology of CAD in human populations.

Pathway-based association methods have been proposed to be an effective approach in identifying disease genes, when single-marker association tests do not have sufficient power. The analysis of quantitative traits may be benefited from these approaches, by sampling from two extreme tails of the distribution. Here we tested a pathway association approach on a small genome-wide association study (GWAS) on 653 subjects with extremely high high-density lipoprotein cholesterol (HDL-C) levels and 784 subjects with low HDL-C levels. We identified 102 genes in the sterol transport and metabolism pathways that collectively associate with HDL-C levels, and replicated these association signals in an independent GWAS. Interestingly, the pathways include 18 genes implicated in previous GWAS on lipid traits, suggesting that genuine HDL-C genes are highly enriched in these pathways. Additionally, multiple biologically relevant loci in the pathways were not detected by previous GWAS, including genes implicated in previous candidate gene association studies (such as LEPR, APOA2, HDLBP, SOAT2), genes that cause Mendelian forms of lipid disorders (such as DHCR24), and genes expressing dyslipidemia phenotypes in knockout mice (such as SOAT1, PON1). Our study suggests that sampling from two extreme tails of a quantitative trait and examining genetic pathways may yield biological insights from smaller samples than are generally required using single-marker analysis in large-scale GWAS. Our results also implicate that functionally related genes work together to regulate complex quantitative traits, and that future large-scale studies may benefit from pathway-association approaches to identify novel pathways regulating HDL-C levels.

Objective

Plasma adiponectin is strongly associated with various components of metabolic syndrome, type 2 diabetes and cardiovascular outcomes. Concentrations are highly heritable and differ between men and women. We therefore aimed to investigate the genetics of plasma adiponectin in men and women.

Methods

We combined genome-wide association scans of three population-based studies including 4659 persons. For the replication stage in 13795 subjects, we selected the 20 top signals of the combined analysis, as well as the 10 top signals with p-values less than 1.0*10-4 for each the men- and the women-specific analyses. We further selected 73 SNPs that were consistently associated with metabolic syndrome parameters in previous genome-wide association studies to check for their association with plasma adiponectin.

Results

The ADIPOQ locus showed genome-wide significant p-values in the combined (p=4.3*10-24) as well as in both women- and men-specific analyses (p=8.7*10-17 and p=2.5*10-11, respectively). None of the other 39 top signal SNPs showed evidence for association in the replication analysis. None of 73 SNPs from metabolic syndrome loci exhibited association with plasma adiponectin (p>0.01).

Conclusions

We demonstrated the ADIPOQ gene as the only major gene for plasma adiponectin, which explains 6.7% of the phenotypic variance. We further found that neither this gene nor any of the metabolic syndrome loci explained the sex differences observed for plasma adiponectin. Larger studies are needed to identify more moderate genetic determinants of plasma adiponectin.

Summary

Background

LDL cholesterol has a causal role in the development of cardiovascular disease. Improved understanding of the biological mechanisms that underlie the metabolism and regulation of LDL cholesterol might help to identify novel therapeutic targets. We therefore did a genome-wide association study of LDL-cholesterol concentrations.

Methods

We used genome-wide association data from up to 11 685 participants with measures of circulating LDL-cholesterol concentrations across five studies, including data for 293 461 autosomal single nucleotide polymorphisms (SNPs) with a minor allele frequency of 5% or more that passed our quality control criteria. We also used data from a second genome-wide array in up to 4337 participants from three of these five studies, with data for 290 140 SNPs. We did replication studies in two independent populations consisting of up to 4979 participants. Statistical approaches, including meta-analysis and linkage disequilibrium plots, were used to refine association signals; we analysed pooled data from all seven populations to determine the effect of each SNP on variations in circulating LDL-cholesterol concentrations.

Findings

In our initial scan, we found two SNPs (rs599839 [p=1·7×10−15] and rs4970834 [p=3·0×10−11]) that showed genome-wide statistical association with LDL cholesterol at chromosomal locus 1p13.3. The second genome screen found a third statistically associated SNP at the same locus (rs646776 [p=4·3×10−9]). Meta-analysis of data from all studies showed an association of SNPs rs599839 (combined p=1·2×10−33) and rs646776 (p=4·8×10−20) with LDL-cholesterol concentrations. SNPs rs599839 and rs646776 both explained around 1% of the variation in circulating LDL-cholesterol concentrations and were associated with about 15% of an SD change in LDL cholesterol per allele, assuming an SD of 1 mmol/L.

Interpretation

We found evidence for a novel locus for LDL cholesterol on chromosome 1p13.3. These results potentially provide insight into the biological mechanisms that underlie the regulation of LDL cholesterol and might help in the discovery of novel therapeutic targets for cardiovascular disease.

The timing of puberty is highly variable1. We carried out a genome-wide association study for age at menarche in 4,714 women and report an association in LIN28B on chromosome 6 (rs314276, minor allele frequency (MAF) = 0.33, P = 1.5 × 10−8). In independent replication studies in 16,373 women, each major allele was associated with 0.12 years earlier menarche (95% CI = 0.08–0.16; P = 2.8 × 10−10; combined P = 3.6 × 10−16). This allele was also associated with earlier breast development in girls (P = 0.001; N = 4,271); earlier voice breaking (P = 0.006, N = 1,026) and more advanced pubic hair development in boys (P = 0.01; N = 4,588); a faster tempo of height growth in girls (P = 0.00008; N = 4,271) and boys (P = 0.03; N = 4,588); and shorter adult height in women (P = 3.6 × 10−7; N = 17,274) and men (P = 0.006; N = 9,840) in keeping with earlier growth cessation. These studies identify variation in LIN28B, a potent and specific regulator of microRNA processing2, as the first genetic determinant regulating the timing of human pubertal growth and development.

Context:

Plasma levels of C-reactive protein (CRP) are independently associated with risk of coronary heart disease, but whether CRP is causally associated with coronary heart disease or merely a marker of underlying atherosclerosis is uncertain.

Objective:

To investigate association of genetic loci with CRP levels and risk of coronary heart disease.

Design, setting and participants:

We first carried out a genome-wide association (n=17,967) and replication study (n=14,747) to identify genetic loci associated with plasma CRP concentrations. Data collection took place between 1989 and 2008 and genotyping between 2003 and 2008. We carried out a Mendelian randomisation study of the most closely associated SNP in the CRP locus and published data on other CRP variants involving a total of 28,112 cases and 100,823 controls, to investigate the association of CRP variants with coronary heart disease. We compared our finding with that predicted from meta-analysis of observational studies of CRP levels and risk of coronary heart disease. For the other loci associated with CRP levels, we selected the most closely associated SNP for testing against coronary heart disease among 14,365 cases and 32,069 controls.

Main outcome measure:

Risk of coronary heart disease.

Results:

Polymorphisms in five genetic loci were strongly associated with CRP levels (% difference per minor allele): SNP rs6700896 in LEPR (−14.7% [95% Confidence Interval {CI}], −17.5 – −11.9, P=1.6×10−21), rs4537545 in IL6R (−10.8% [95% CI, −13.8 – −7.7], P=5.1×10−11), rs7553007 in CRP locus (−20.7% [95% CI, −23.5 – −17.9], P=3.3×10−38), rs1183910 in HNF1A (−13.6% [95% CI, −16.4 – −10.6], P=1.2×10−17) and rs4420638 in APOE-CI-CII (−21.8% [95% CI, −25.4 – −18.1], P=2.1×10−25). Association of SNP rs7553007 in the CRP locus with coronary heart disease gave odds ratio (OR) 0.98 (95% CI, 0.94 – 1.01) per 20% lower CRP. Our Mendelian randomisation study of variants in the CRP locus showed no association with coronary heart disease: OR 1.00 (95% CI, 0.97 – 1.02) per 20% lower CRP, compared with OR 0.94 (95% CI, 0.94 – 0.95) predicted from meta-analysis of the observational studies of CRP levels and coronary heart disease (Z-score −3.45, P<.001). SNPs rs6700896 in LEPR (OR 1.06 [95% CI, 1.02 – 1.09] per minor allele), rs4537545 in IL6R (OR 0.94 [95% CI, 0.91 – 0.97]) and rs4420638 in the APOE-CI-CII cluster (OR 1.16 [95% CI, 1.12 – 1.21]) were all associated with risk of coronary heart disease.

Conclusions:

The lack of concordance between the effect on coronary heart disease risk of CRP genotypes and CRP levels argues against a causal association of CRP with coronary heart disease.

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.

Background

The P-glycoprotein, encoded by the ABCB1 gene, is expressed in human endothelial and mesangial cells, which contribute to control renal plasma flow and glomerular filtration rate. We investigated the association of ABCB1 variants with renal function in African and Caucasian subjects.

Methods

In Africans (290 subjects from 62 pedigrees), we genotyped the 2677G>T and 3435 C>T ABCB1 polymorphisms. Glomerular filtration rate (GFR) was measured using inulin clearance and effective renal plasma flow (ERPF) using para-aminohippurate clearance. In Caucasians (5382 unrelated subjects), we analyzed 30 SNPs located within and around ABCB1, using data from the Affymetrix 500 K chip. GFR was estimated using the simplified Modification of the Diet in Renal Disease (MDRD) and Cockcroft-Gault equations.

Results

In Africans, compared to the reference genotype (GG or CC), each copy of the 2677T and 3435T allele was associated, respectively, with: GFR higher by 10.6 ± 2.9 (P < 0.001) and 4.4 ± 2.3 (P = 0.06) mL/min; ERPF higher by 47.5 ± 11.6 (P < 0.001) and 28.1 ± 10.5 (P = 0.007) mL/min; and renal resistances lower by 0.016 ± 0.004 (P < 0.001) and 0.011 ± 0.004 (P = 0.004) mm Hg/mL/min. In Caucasians, we identified 3 polymorphisms in the ABCB1 gene that were strongly associated with all estimates of GFR (smallest P value = 0.0006, overall P = 0.014 after multiple testing correction).

Conclusion

Variants of the ABCB1 gene were associated with renal function in both Africans and Caucasians and may therefore confer susceptibility to nephropathy in humans. If confirmed in other studies, these results point toward a new candidate gene for nephropathy in humans.