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Recent genome-wide association (GWA) studies described 95 loci controlling serum lipid levels. These common variants explain ∼25% of the heritability of the phenotypes. To date, no unbiased screen for gene-environment interactions for circulating lipids has been reported. We screened for variants that modify the relationship between known epidemiological risk factors and circulating lipid levels in a meta-analysis of genome-wide association (GWA) data from 18 population-based cohorts with European ancestry (maximum N = 32,225). We collected 8 further cohorts (N = 17,102) for replication, and rs6448771 on 4p15 demonstrated genome-wide significant interaction with waist-to-hip-ratio (WHR) on total cholesterol (TC) with a combined P-value of 4.79×10(-9). There were two potential candidate genes in the region, PCDH7 and CCKAR, with differential expression levels for rs6448771 genotypes in adipose tissue. The effect of WHR on TC was strongest for individuals carrying two copies of G allele, for whom a one standard deviation (sd) difference in WHR corresponds to 0.19 sd difference in TC concentration, while for A allele homozygous the difference was 0.12 sd. Our findings may open up possibilities for targeted intervention strategies for people characterized by specific genomic profiles. However, more refined measures of both body-fat distribution and metabolic measures are needed to understand how their joint dynamics are modified by the newly found locus.

We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS) < 10(-4) and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome-wide significance (P(combined) < 5 x 10(-8)); most contain genes with immune functions (BACH2, CCR4, CD80, CIITA-SOCS1-CLEC16A, ICOSLG and ZMIZ1), with ETS1, RUNX3, THEMIS and TNFRSF14 having key roles in thymic T-cell selection. There was evidence to suggest associations for a further 13 regions. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P < 0.0028, FDR 5%) with cis gene expression.

Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2 (P = 1 × 10(-23)), FGF5 (P = 1 × 10(-21)), SH2B3 (P = 3 × 10(-18)), MTHFR (P = 2 × 10(-13)), c10orf107 (P = 1 × 10(-9)), ZNF652 (P = 5 × 10(-9)) and PLCD3 (P = 1 × 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

BackgroundThe neuronal ceroid lipofuscinoses (NCL) are a group of children's inherited neurodegenerative disorders, characterized by blindness, early dementia and pronounced cortical atrophy. The similar pathological and clinical profiles of the different forms of NCL suggest that common disease mechanisms may be involved. To explore the NCL-associated disease pathology and molecular pathways, we have previously produced targeted knock-out mice for Cln1 and Cln5. Both mouse-models replicate the NCL phenotype and neuropathology; the Cln1-/- model presents with early onset, severe neurodegenerative disease, whereas the Cln5-/- model produces a milder disease with a later onset.ResultsHere we have performed quantitative gene expression profiling of the cortex from 1 and 4 month old Cln1-/- and Cln5-/- mice. Combined microarray datasets from both mouse models exposed a common affected pathway: genes regulating neuronal growth cone stabilization display similar aberrations in both models. We analyzed locus specific gene expression and showed regional clustering of Cln1 and three major genes of this pathway, further supporting a close functional relationship between the corresponding gene products; adenylate cyclase-associated protein 1 (Cap1), protein tyrosine phosphatase receptor type F (Ptprf) and protein tyrosine phosphatase 4a2 (Ptp4a2). The evidence from the gene expression data, indicating changes in the growth cone assembly, was substantiated by the immunofluorescence staining patterns of Cln1-/- and Cln5-/- cortical neurons. These primary neurons displayed abnormalities in cytoskeleton-associated proteins actin and beta-tubulin as well as abnormal intracellular distribution of growth cone associated proteins GAP-43, synapsin and Rab3.ConclusionOur data provide the first evidence for a common molecular pathogenesis behind neuronal degeneration in INCL and vLINCL. Since CLN1 and CLN5 code for proteins with distinct functional roles these data may have implications for other forms of NCLs as well.

A novel approach to finding candidate genes by using gene expression data through liquid association is developed and used to identify multiple sclerosis susceptibility candidate genes.

A unique resource of longitudinal childhood height data available in Finnish population cohorts was used to study the largely unknown genetic underpinnings of height growth. The partially correlated variants at LIN28B which influence the entire period of postnatal growth implied a critical role for LIN28B in the regulation of human growth.

A genome-wide association approach to study 1507 children from the Avon Longitudinal Study of Parents and Children (ALSPAC) was applied to identify genetic determinants underlying variation in 2D:4D. The results demonstrated that a variant within the LIN28B gene is associated with 2D:4D and is significant for the early development of the hands and is also associated with height and age at menarche.

A genome-wide association study is undertaken in a high-risk isolate for multiple sclerosis (MS) in order to identify previously unreported high-impact variants associated with MS. Results reveal that SNP (rs744166) within the STAT3 gene is associated with MS.

The study results from two genome-wide association studies (GWASs) for serum markers of iron status that are important in iron overload and deficiency conditions are reported. The results are applied for understanding the iron metabolism and regulation of hepatic protein secretion and also the genetic architecture of some endophenotypes that might be simpler than that of disease.

An example of one of the best-known founder populations is scrutinized to prove that the genome-wide patterns of variation lead to a significant substructure in a founder population. The results of the study prove that the consecutive founder effects highly support the concept of multiple historical bottlenecks in populations.

Defects in expression of genes of oxidative phosphorylation in mitochondria have been suggested to be a key pathophysiological feature in familial insulin resistance. We examined whether such defects can arise from lifestyle-related factors alone. Fourteen obesity-discordant (BMI difference 5.2 [+ or -] 1.8 kg/[m.sup.2]) and 10 concordant (1.0 [+ or -] 0.7 kg/[m.sup.2]) monozygotic (MZ) twin pairs aged 24-27 yr were identified among 658 MZ pairs in the population-based FinnTwin 16 study. Whole body insulin sensitivity was measured using the euglycemic hyperinsulinemic clamp technique. Transcript profiles of mitochondrial genes were compared using microarray data of fat biopsies from discordant twins. Body composition of twins was determined using DEXA and maximal oxygen uptake (V[o.sub.2max]) and working capacity ([W.sub.max]) using a bicycle ergometer exercise test with gas exchange analysis. The obese cotwins had lower insulin sensitivity than their nonobese counterparts (M value 6.1 [+ or -] 2.0 vs. 9.2 [+ or -] 3.2 mg * kg LB[M.sup.-1] * [min.sup.-1], P < 0.01). Transcript levels of genes involved in the oxidative phosphorylation pathway (GO:0006119) in adipose tissue were lower (P < 0.05) in the obese compared with the nonobese cotwins. The obese cotwins were also less fit, as measured by V[o.sub.2max] (50.6 [+ or -] 6.5 vs. 54.2 [+ or -] 6.4 ml * kg LB[M.sup.-1] * [min.sup.-1], for obese vs. nonobese, P < 0.05), [W.sub.max] (3.9 [+ or -] 0.5 vs. 4.4 [+ or -] 0.7 W/kg LBM, P < 0.01) and also less active, by the Baecke leisure time physical activity index (2.8 [+ or -] 0.5 vs. 3.3 [+ or -] 0.6, P < 0.01). This implies that acquired poor physical fitness is associated with defective expression of the oxidative pathway components in adipose tissue mitochondria. body composition; cardiorespiratory fitness; spiroergometry; gene expression

The identification of sixth and the fifth gene, CC2D2A (MKS6), behind Meckel syndrome (MKS), a lethal malformation disorder based on the homozygous regions shared by MKS genes. Results for molecular background of MKS and function of cilia could help to better understand the significance of cilia in early human development and other ciliopathies.

The article discusses the results obtained from two genome-wide studies, where in several migraine-phenotyping methods detect and replicate a locus on 10q22-q23. The 10q22-q23 locus is shown to contain one or more of the migraine susceptibility variants.

Background The acquired component of complex traits is difficult to dissect in humans. Obesity represents such a trait, in which the metabolic and molecular consequences emerge from complex interactions of genes and environment. With the substantial morbidity associated with obesity, a deeper understanding of the concurrent metabolic changes is of considerable importance. The goal of this study was to investigate this important acquired component and expose obesity-induced changes in biological pathways in an identical genetic background. Methods and Findings We used a special study design of 'clonal controls,' rare monozygotic twins discordant for obesity identified through a national registry of 2,453 young, healthy twin pairs. A total of 14 pairs were studied (eight male, six female; white), with a mean ± standard deviation (SD) age 25.8 ± 1.4 y and a body mass index (BMI) difference 5.2 ± 1.8 kg/[m.sup.2]. Sequence analyses of mitochondrial DNA (mtDNA) in subcutaneous fat and peripheral leukocytes revealed no aberrant heteroplasmy between the co-twins. However, mtDNA copy number was reduced by 47% in the obese co-twin's fat. In addition, novel pathway analyses of the adipose tissue transcription profiles exposed significant down-regulation of mitochondrial branched-chain amino acid (BCAA) catabolism (p < 0.0001). In line with this finding, serum levels of insulin secretion-enhancing BCAAs were increased in obese male co-twins (9% increase, p = 0.025). Lending clinical relevance to the findings, in both sexes the observed aberrations in mitochondrial amino acid metabolism pathways in fat correlated closely with liver fat accumulation, insulin resistance, and hyperinsulinemia, early aberrations of acquired obesity in these healthy young adults. Conclusions Our findings emphasize a substantial role of mitochondrial energy- and amino acid metabolism in obesity and development of insulin resistance. doi:10.1371/journal.pmed.0050051, Introduction Adipose tissue is a key player in obesity-related metabolic dysfunctions, and is closely linked to other peripheral organs that control energy flux [1]. To understand the pathogenesis of adipose [...]

Two new mutations are identified among Saudis who are known for high prevalence of lactase persistence (LP). It is found to support the convergent evolution of LP in diverse populations, reflecting different histories of adaptation to milk culture.

The background of the alleles carrying the critical variant in 1611 DNA samples from 37 populations were analyzed and concluded that the [T.sub.-13910] allele was independently introduced more than once.

A genomewide linkage screen of simple heavy-smoking quantitative trait is conducted using two independent samples. The study found significant evidence of linkage to chromosome 20 in the Finnish sample.

A family-based candidate-gene study assesses maternal-fetal genotype matching at human leucocyte antigen-A (HLA-A), -B and -DRB1 as a risk factor of schizophrenia in offspring. The approach demonstrates the use of genetic markers to characterize the biology of prenatal risk factors of schizophrenia, and findings support the neurodevelopmental hypothesis of schizophrenia, and also suggest that the prenatal period is involved in the origin of this disease.

Research has been conducted on the low peak mass that presents significant risk factor for osteoporosis. The effect of the LRP5 encoding the low-density lipoprotein receptor-related protein 5 on the bone mass accrual during growth has been investigated and the results are reported.

A genomewide scan for familial combined hyperlipidemia (FCHL) genes has been carried out in 35 Finnish families. Results suggest multiple susceptibility loci influencing cholesterol, triglyceride and apolipoprotein B levels. FCHL is a common dyslipidemia predisposing to early coronary heart disease. It is characterized by higher levels of serum total cholesterol, triglycerides, or both. The first locus was recently found to be on chromosome 1q21-q23.

Studies support a link between Marfan syndrome and parental genetic origin. This connective tissue disorder has been identified through genotyping, but required sensitive and quantitative solid-phase minisequencing to eliminate possible carrier locations. Since the mutation could not be identified in a paternal sperm sample, the mosaicism may be maternal in origin.

The assignment of a locus for a new lethal neonatal metabolic syndrome made to 2q33-37 is discussed. The autosomal recessively inherited syndrome, for which 17 cases have been reported in 12 families in Finland, is characterized by fulminant lactic acidosis in the first day of life, intrauterine growth retardation, liver hemosiderosis, aminoaciduria and early death, and pathogenesis is not known.

Studies of Finnish subjects show that the autosomal recessive disorder congenital lactase deficiency is linked to a single major mutation. Haplotype analysis and genealogical research reveal the locus of the disease to be near to but separate from the gene lactase-phlorizin hydrolase, which has been ruled out as a causative factor.

The pattern of Y chromosome variation among Finns supports the dual origin hypothesis. Phylogenetic study of 77 haplotype configurations from 280 unrelated males from nine provinces suggests a population expansion from two common Y haplotypes. Significant differences between eastern and western areas of Finland with respect to Y haplotype variation are found. The archaeological evidence supports the results.

Tibial muscular dystrophy (TMD) has been studied by carrying out a genomewide scan with 279 very polymorphic Cooperative Human Linkage Center microsatellite markers on 11 affected people in a Finnish family. In linkage analyses carried out with three other Finnish TMD families using a denser set of markers a maximum two-point LOD score of 10.14 (recombination fraction of .05) was found with marker D2364. The TMD locus was limited to an about 1pcM critical chromosomal region with no evidence of heterogeneity. The evidence for linkage was found from markers in a 43-cM region on chromosome 2q. TMD is a relatively mild rare autosomal dominant distal myopathy of the late adult years.

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLO-SL) is a recessively inherited disorder of unknown pathogenesis involving systemic bone cysts and progressive presenile frontal-lobe dementia and death before the age of 50. Mostly in Japan and Finland, 160 cases have been reported since the 1960s. The locus for PLO-SL has been found by random genome screening using a modified haplotype-sharing method in patients in a genetically isolated group and it is in a 9-cM interval between D19S191 and D19S420 on chromosome 19q13.

Background: One of the most robust genetic associations for cardiovascular disease (CVD) is the Chromosome 9p21 region. However, the interaction of this locus with environmental factors has not been extensively explored. We investigated the association of 9p21 with myocardial infarction (MI) in individuals of different ethnicities, and tested for an interaction with environmental factors. Methods and Findings: We genotyped four 9p21 SNPs in 8,114 individuals from the global INTERHEART study. All four variants were associated with MI, with odds ratios (ORs) of 1.18 to 1.20 (1.85 x [10.sup.-8] [less than or equal to] p [less than or equal to] 5.21 x [10.sup.-7]). A significant interaction (p = 4.0 x [10.sup.-4]) was observed between rs2383206 and a factor-analysis-derived 'prudent' diet pattern score, for which a major component was raw vegetables. An effect of 9p21 on MI was observed in the group with a low prudent diet score (OR = 1.32, p = 6.82 x [10.sup.-7]), but the effect was diminished in a step-wise fashion in the medium (OR = 1.17, p = 4.9 x [10.sup.-3]) and high prudent diet scoring groups (OR = 1.02, p = 0.68) (p = 0.014 for difference). We also analyzed data from 19,129 individuals (including 1,014 incident cases of CVD) from the prospective FINRISK study, which used a closely related dietary variable. In this analysis, the 9p21 risk allele demonstrated a larger effect on CVD risk in the groups with diets low or average for fresh vegetables, fruits, and berries (hazard ratio [HR]=1.22, p = 3.0 x [10.sup.-4], and HR=1.35, p = 4.1 x [10.sup.-3], respectively) compared to the group with high consumption of these foods (HR = 0.96, p = 0.73) (p = 0.0011 for difference). The combination of the least prudent diet and two copies of the risk allele was associated with a 2-fold increase in risk for MI (OR = 1.98, p = 2.11 x [10.sup.-9]) in the INTERHEART study and a 1.66-fold increase in risk for CVD in the FINRISK study (HR=1.66, p = 0.0026). Conclusions: The risk of MI and CVD conferred by Chromosome 9p21 SNPs appears to be modified by a prudent diet high in raw vegetables and fruits., Introduction Cardiovascular disease (CVD), including myocardial infarction (MI), is one of the leading causes of death and disability worldwide [1]. The etiology of the disease is well characterized and includes [...]