Päivi Lahermo

Mutations in AXIN2 Cause Familial Tooth Agenesis and Predispose to Colorectal Cancer

Wnt signaling regulates embryonic pattern formation and morphogenesis of most organs. Aberrations of regulation of Wnt signaling may lead to cancer. Here, we have used positional cloning to identify the causative mutation in a Finnish family in which severe permanent tooth agenesis (oligodontia) and colorectal neoplasia segregate with dominant inheritance. Eleven members of the family lacked at least eight permanent teeth, two of whom developed only three permanent teeth. Colorectal cancer or precancerous lesions of variable types were found in eight of the patients with oligodontia. We show that oligodontia and predisposition to cancer are caused by a nonsense mutation, Arg656Stop, in the Wnt-signaling regulator AXIN2. In addition, we identified a de novo frameshift mutation 1994-1995insG in AXIN2 in an unrelated young patient with severe tooth agenesis. Both mutations are expected to activate Wnt signaling. The results provide the first evidence of the importance of Wnt signaling for the development of dentition in humans and suggest that an intricate control of Wnt-signal activity is necessary for normal tooth development, since both inhibition and stimulation of Wnt signaling may lead to tooth agenesis. Our findings introduce a new gene for hereditary colorectal cancer and suggest that tooth agenesis may be an indicator of cancer susceptibility.

Susceptibility Loci for Preeclampsia on Chromosomes 2p25 and 9p13 in Finnish Families

Preeclampsia is a common, pregnancy-specific disorder characterized by reduced placental perfusion, endothelial dysfunction, elevated blood pressure, and proteinuria. The pathogenesis of this heterogeneous disorder is incompletely understood, but it has a familial component, which suggests that one or more common alleles may act as susceptibility genes. We hypothesized that, in a founder population, the genetic background of preeclampsia might also show reduced heterogeneity, and we have performed a genomewide scan in 15 multiplex families recruited predominantly in the Kainuu province in central eastern Finland. We found two loci that exceeded the threshold for significant linkage: chromosome 2p25, near marker D2S168 (nonparametric linkage [NPL] score 3.77; P=.000761) at 21.70 cM, and 9p13, near marker D9S169 (NPL score 3.74; P=.000821) at 38.90 cM. In addition, there was a locus showing suggestive linkage at chromosome 4q32 between D4S413 and D4S3046 (NPL score 3.13; P=.003238) at 163.00 cM. In the present study the susceptibility locus on chromosome 2p25 is clearly different (21.70 cM) from the locus at 2p12 found in an Icelandic study (94.05 cM) and the locus at 2q23 (144.7 cM) found in an Australian/New Zealand study. The locus at 9p13 has been shown to be a candidate region for type 2 diabetes in two recently published genomewide scans from Finland and China. The regions on chromosomes 2p25 and 9p13 may harbor susceptibility genes for preeclampsia.

A genome scan for developmental dyslexia confirms linkage to chromosome 2p11 and suggests a new locus on 7q32

Developmental dyslexia is a distinct learning disability with unexpected difficulty in learning to read despite adequate intelligence, education, and environment, and normal senses. The genetic aetiology of dyslexia is heterogeneous and loci on chromosomes 2, 3, 6, 15, and 18 have been repeatedly linked to it. We have conducted a genome scan with 376 markers in 11 families with 38 dyslexic subjects ascertained in Finland. Linkage of dyslexia to the vicinity of DYX3 on 2p was confirmed with a non-parametric linkage (NPL) score of 2.55 and a lod score of 3.01 for a dominant model, and a novel locus on 7q32 close to the SPCH1 locus was suggested with an NPL score of 2.77. The SPCH1 locus has previously been linked with a severe speech and language disorder and autism, and a mutation in exon 14 of the FOXP2 gene on 7q32 has been identified in one large pedigree. Because the language disorder associated with the SPCH1 locus has some overlap with the language deficits observed in dyslexia, we sequenced the coding region of FOXP2 as a candidate gene for our observed linkage in six dyslexic subjects. No mutations were identified. We conclude that DYX3 appears to be important for dyslexia susceptibility in many Finnish families, and a suggested linkage of dyslexia to chromosome 7q32 will need verification in other data sets.

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 (FST = 0.0040, p<10−4), also between Eastern and Western Finland (FST = 0.0032, p<10−3). The latter indicated the existence of a relatively strong autosomal substructure within the country, similar to that observed earlier with smaller numbers of markers. The Germans and British were less differentiated than the Swedes, Western Finns and especially the Eastern Finns who also showed other signs of genetic drift. This is likely caused by the later founding of the northern populations, together with subsequent founder and bottleneck effects, and a smaller population size. Furthermore, our data suggest a small eastern contribution among the Finns, consistent with the historical and linguistic background of the population. Significance Our results warn against a priori assumptions of homogeneity among Finns and other seemingly isolated populations. Thus, in association studies in such populations, additional caution for population structure may be necessary. Our results illustrate that population history is often important for patterns of genetic variation, and that the analysis of hundreds of thousands of SNPs provides high resolution also for population genetics.

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. The hierarchical fine mapping in an extended data set with 24 families originating from the same geographic region revealed a shared 110 kb to 13 Mb haplotype on chromosome 4q31, which was significantly more frequent among the patients than in population-based controls (odds ratio 6.3; 95% CI 2.5-15.9; P = .0001). The shared haplotype harbored two functionally uncharacterized genes, ELMOD2 and LOC152586, of which only ELMOD2 was expressed in lung and showed significantly decreased messenger-RNA expression in IPF lung (n = 6) when compared with that of healthy lung (n = 7; P = .05). Our results suggest ELMOD2 as a novel candidate gene for susceptibility in familial IPF.

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%. In Finland, four founder mutations constitute up to 70% of the known genetic spectrum of LQTS. In the present survey, we sought to estimate the actual prevalence of the founder mutations and to determine their effect sizes in the general Finnish population. Methods and results. We genotyped 6334 subjects aged≥30 years from a population cohort (Health 2000 study) for the four Finnish founder mutations using Sequenom MALDI-TOF mass spectrometry. The electrocardiogram (ECG) parameters were measured from digital 12-lead ECGs, and QT intervals were adjusted for age, sex, and heart rate using linear regression. A total of 27 individuals carried one of the founder mutations resulting in their collective prevalence estimate of 0.4% (95% CI 0.3%–0.6%). The KCNQ1 G589D mutation (n=8) was associated with a 50 ms (SE 7.0) prolongation of the adjusted QT interval (P=9.0×10−13). The KCNH2 R176W variant (n=16) resulted in a 22 ms (SE 4.7) longer adjusted QT interval (P=2.1×10−6). Conclusion. In Finland 1 individual out of 250 carries a LQTS founder mutation, which is the highest documented prevalence of LQTS mutations that lead to a marked QT prolongation.

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. SETTING Academic research. PARTICIPANTS Individuals from an unselected birth cohort in Finland. Originally, everyone born in the catchment area in 1966 (N = 12 058) was included in the study. Of these, 4651 (38.6%) attended the 31-year follow-up and could be included in the study. MAIN OUTCOME MEASURES Scores on 4 psychometric instruments selected to function as proxies for positive and negative aspects of psychotic disorders, including the Perceptual Aberration Scale, Revised Social Anhedonia Scale, Revised Physical Anhedonia Scale, and Schizoidia Scale by Golden and Meehl. RESULTS Carriers of the minor allele of marker rs821577 had significantly higher scores on social anhedonia (P < .001). The minor allele of marker rs821633 was strongly associated with lower scores on social anhedonia when analyzed dependent on the absence of the minor alleles of markers rs1538979 and rs821577 (P < .001). CONCLUSIONS Variants in DISC1 affect the level of social anhedonia, a cardinal symptom of schizophrenia in the general population. DISC1 might be more central to human psychological functioning than previously thought, as it seems to affect the degree to which people enjoy social interactions.

Mapping of the second locus for the Van der Woude syndrome to chromosome 1p34

The Van der Woude syndrome (VWS) is a dominantly inherited developmental disorder characterized by pits and/or sinuses of the lower lip, cleft lip and/or cleft palate. It is the most common cleft syndrome. VWS has shown remarkable genetic homogeneity in all populations, and so far, all families reported have been linked to 1q32-q41. A large Finnish pedigree with VWS was recently found to be unlinked to 1q32-q41. In order to map the disease locus in this family, a genome wide linkage scan was performed. A maximum lod score of 3.18 was obtained with the marker D1S2797, thus assigning the disease locus to chromosomal region 1p34. By analyses of meiotic recombinants an ∼30 cM region of shared haplotypes was identified. The results confirm the heterogeneity of the VWS syndrome, and they place the second disease locus in 1p34. This finding has a special interest because the phenotype in VWS closely resembles the phenotype in non-syndromic forms of cleft lip and palate.

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.

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. However, many of the migrations affecting the area from Central Europe, the Volga‐Ural region and from Slavic populations have had a quantitatively different impact on the populations, and, furthermore, the effects of genetic drift have increased the differences between populations especially in the north. The possible explanations for the high frequencies of several haplogroups with an origin in the Iberian refugia (H1, U5b, I1a) are also discussed.