Dominant Distal Myopathy 3 (MPD3) Caused by a Deletion in the Gene.

Background And Objectives: To determine the genetic cause of the disease in the previously reported family with adult-onset autosomal dominant distal myopathy (myopathy, distal, 3; MPD3).

Methods: Continued clinical evaluation including muscle MRI and muscle pathology. A linkage analysis with single nucleotide polymorphism arrays and genome sequencing were used to identify the genetic defect, which was verified by Sanger sequencing.

Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions.

Using deep phenotyping and high-throughput sequencing, we have identified a novel type of distal myopathy caused by mutations in the Small muscle protein X-linked (SMPX) gene. Four different missense mutations were identified in ten patients from nine families in five different countries, suggesting that this disease could be prevalent in other populations as well. Haplotype analysis of patients with similar ancestry revealed two different founder mutations in Southern Europe and France, indicating that the prevalence in these populations may be higher.

Breakpoint mapping and haplotype analysis of translocation t(1;12)(q43;q21.1) in two apparently independent families with vascular phenotypes.

Background: The risk of serious congenital anomaly for de novo balanced translocations is estimated to be at least 6%. We identified two apparently independent families with a balanced t(1;12)(q43;q21.1) as an outcome of a "Systematic Survey of Balanced Chromosomal Rearrangements in Finns.

Two missense mutations in KCNQ1 cause pituitary hormone deficiency and maternally inherited gingival fibromatosis.

Familial growth hormone deficiency provides an opportunity to identify new genetic causes of short stature. Here we combine linkage analysis with whole-genome resequencing in patients with growth hormone deficiency and maternally inherited gingival fibromatosis. We report that patients from three unrelated families harbor either of two missense mutations, c.

New susceptibility loci associated with kidney disease in type 1 diabetes.

Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D). Whereas the degree of glycemia plays a pivotal role in DN, a subset of individuals with poorly controlled T1D do not develop DN.

High-resolution SNP array analysis of patients with developmental disorder and normal array CGH results.

Background: Diagnostic analysis of patients with developmental disorders has improved over recent years largely due to the use of microarray technology. Array methods that facilitate copy number analysis have enabled the diagnosis of up to 20% more patients with previously normal karyotyping results. A substantial number of patients remain undiagnosed, however.

Mutations of complement lectin pathway genes MBL2 and MASP2 associated with placental malaria.

Background: Innate immunity plays a crucial role in the host defense against malaria including Plasmodium falciparum malaria in pregnancy, but the roles of the various underlying genes and mechanisms predisposing to the disease are poorly understood.

Methods: 98 single-nucletoide polymorphisms were genotyped in a set of 17 functionally related genes of the complement system in 145 primiparous Ghanaian women with placental malaria, defined by placental parasitaemia or malaria pigment, and as a control, in 124 non-affected primiparae.

Results: Placental malaria was significantly associated with SNPs in the lectin pathway genes MBL2, MASP2, FCN2 and in properdin.

Methylation of H19 and its imprinted control region (H19 ICR1) in Müllerian aplasia.

Severe hypomethylation of the H19 imprinted control region (ICR1) in two patients with Silver-Russell syndrome (SRS) who have genital malformations has encouraged us to study DNA methylation in a cohort of 83 patients with Müllerian aplasia (MA). Site-specific methylation analyses of H19 ICR1 by quantitative real-time polymerase chain reaction in 80 clinically well-diagnosed Finnish MA patients showed no association between hypomethylation and the MA phenotype, but studies of the H19 locus in 38 patients showed aberrant methylation in 3/16 studied sites.

Swedish population substructure revealed by genome-wide single nucleotide polymorphism data.

The use of genome-wide single nucleotide polymorphism (SNP) data has recently proven useful in the study of human population structure. We have studied the internal genetic structure of the Swedish population using more than 350,000 SNPs from 1525 Swedes from all over the country genotyped on the Illumina HumanHap550 array. We have also compared them to 3212 worldwide reference samples, including Finns, northern Germans, British and Russians, based on the more than 29,000 SNPs that overlap between the Illumina and Affymetrix 250K Sty arrays.

European lactase persistence genotype shows evidence of association with increase in body mass index.

The global prevalence of obesity has increased significantly in recent decades, mainly due to excess calorie intake and increasingly sedentary lifestyle. Here, we test the association between obesity measured by body mass index (BMI) and one of the best-known genetic variants showing strong selective pressure: the functional variant in the cis-regulatory element of the lactase gene. We tested this variant since it is presumed to provide nutritional advantage in specific physical and cultural environments.

Genomic landscape of positive natural selection in Northern European populations.

Analyzing genetic variation of human populations for detecting loci that have been affected by positive natural selection is important for understanding adaptive history and phenotypic variation in humans. In this study, we analyzed recent positive selection in Northern Europe from genome-wide data sets of 250 000 and 500 000 single-nucleotide polymorphisms (SNPs) in a total of 999 individuals from Great Britain, Northern Germany, Eastern and Western Finland, and Sweden. Coalescent simulations were used for demonstrating that the integrated haplotype score (iHS) and long-range haplotype (LRH) statistics have sufficient power in genome-wide data sets of different sample sizes and SNP densities.

Association between genes of Disrupted in schizophrenia 1 (DISC1) interactors and schizophrenia supports the role of the DISC1 pathway in the etiology of major mental illnesses.

Background: Disrupted in Schizophrenia 1 (DISC1) is currently one of the most interesting candidate genes for major mental illness, having been demonstrated to associate with schizophrenia, bipolar disorder, major depression, autism, and Asperger's syndrome. We have previously reported a DISC1 haplotype, HEP3, and an NDE1 spanning tag haplotype to associate to schizophrenia in Finnish schizophrenia families. Because both DISC1 and NDE1 display association in our study sample, we hypothesized that other genes interacting with DISC1 might also have a role in the etiology of schizophrenia.

Association of variants in DISC1 with psychosis-related traits in a large population cohort.

Context: There is an abundance of data from human genetic studies and animal models that implies a role for the disrupted in schizophrenia 1 gene (DISC1) in the etiology of schizophrenia and other major mental illnesses.

Objective: To study the effect of previously identified risk alleles of DISC1 on quantitative intermediate phenotypes for psychosis in an unselected population.

Design: We examined 41 single-nucleotide polymorphisms within DISC1 and performed tests of association with 4 quantitative phenotypes.

High prevalence of four long QT syndrome founder mutations in the Finnish population.

Aims: Long QT syndrome (LQTS) is an inherited arrhythmia disorder with an estimated prevalence of 0.01%-0.05%.

Population structure in contemporary Sweden--a Y-chromosomal and mitochondrial DNA analysis.

A population sample representing the current Swedish population was analysed for maternally and paternally inherited markers with the aim of characterizing genetic variation and population structure. The sample set of 820 females and 883 males were extracted and amplified from Guthrie cards of all the children born in Sweden during one week in 2003. 14 Y-chromosomal and 34 mitochondrial DNA SNPs were genotyped.

Common candidate gene variants are associated with QT interval duration in the general population.

Objectives: QT interval prolongation is associated with increased risk of sudden cardiac death at the population level. As 30-40% of the QT-interval variability is heritable, we tested the association of common LQTS and NOS1AP gene variants with QT interval in a Finnish population-based sample.

Methods: We genotyped 12 common LQTS and NOS1AP genetic variants in Health 2000, an epidemiological sample of 5043 Finnish individuals, using Sequenom MALDI-TOF mass spectrometry.

Genome-wide analysis of single nucleotide polymorphisms uncovers population structure in Northern Europe.

Background: Genome-wide data provide a powerful tool for inferring patterns of genetic variation and structure of human populations.

Principal Findings: In this study, we analysed almost 250,000 SNPs from a total of 945 samples from Eastern and Western Finland, Sweden, Northern Germany and Great Britain complemented with HapMap data. Small but statistically significant differences were observed between the European populations (F(ST) = 0.

Population substructure in Finland and Sweden revealed by the use of spatial coordinates and a small number of unlinked autosomal SNPs.

Background: Despite several thousands of years of close contacts, there are genetic differences between the neighbouring countries of Finland and Sweden. Within Finland, signs of an east-west duality have been observed, whereas the population structure within Sweden has been suggested to be more subtle. With a fine-scale substructure like this, inferring the cluster membership of individuals requires a large number of markers.

Migration waves to the Baltic Sea region.

In this study, the population history of the Baltic Sea region, known to be affected by a variety of migrations and genetic barriers, was analyzed using both mitochondrial DNA and Y-chromosomal data. Over 1200 samples from Finland, Sweden, Karelia, Estonia, Setoland, Latvia and Lithuania were genotyped for 18 Y-chromosomal biallelic polymorphisms and 9 STRs, in addition to analyzing 17 coding region polymorphisms and the HVS1 region from the mtDNA. It was shown that the populations surrounding the Baltic Sea are genetically similar, which suggests that it has been an important route not only for cultural transmission but also for population migration.

A quality assessment survey of SNP genotyping laboratories.

To survey the quality of SNP genotyping, a joint Nordic quality assessment (QA) round was organized between 11 laboratories in the Nordic and Baltic countries. The QA round involved blinded genotyping of 47 DNA samples for 18 or six randomly selected SNPs. The methods used by the participating laboratories included all major platforms for small- to medium-size SNP genotyping.

ELMOD2 is a candidate gene for familial idiopathic pulmonary fibrosis.

We performed a genomewide scan in six multiplex families with familial idiopathic pulmonary fibrosis (IPF) who originated from southeastern Finland. The majority of the Finnish multiplex families were clustered in the region, and the population history suggested that the clustering might be explained by an ancestor shared among the patients. The genomewide scan identified five loci of interest.