Liu, F.

Comprehensive candidate gene study highlights UGT1A and BNC2 as new genes determining continuous skin color variation in Europeans (Article)

2012-10-11T00:00:00Z

Natural variation in human skin pigmentation is primarily due to genetic causes rooted in recent evolutionary history. Genetic variants associated with human skin pigmentation confer risk of skin cancer and may provide useful information in forensic investigations. Almost all previous gene-mapping studies of human skin pigmentation were based on categorical skin color information known to oversimplify the continuous nature of human skin coloration. We digitally quantified skin color into hue and saturation dimensions for 5,860 Dutch Europeans based on high-resolution skin photographs. We then tested an extensive list of 14,185 single nucleotide polymorphisms in 281 candidate genes potentially involved in human skin pigmentation for association with quantitative skin color phenotypes. Confirmatory association was revealed for several known skin color genes including HERC2, MC1R, IRF4, TYR, OCA2, and ASIP. We identified two new skin color genes: genetic variants in UGT1A were significantly associated with hue and variants in BNC2 were significantly associated with saturation. Overall, digital quantification of human skin color allowed detecting new skin color genes. The variants identified in this study may also contribute to the risk of skin cancer. Our findings are also important for predicting skin color in forensic investigations.

Detecting low frequent loss-of-function alleles in genome wide association studies with red hair color as example (Article)

2011-11-29T00:00:00Z

Multiple loss-of-function (LOF) alleles at the same gene may influence a phenotype not only in the homozygote state when alleles are considered individually, but also in the compound heterozygote (CH) state. Such LOF alleles typically have low frequencies and moderate to large effects. Detecting such variants is of interest to the genetics community, and relevant statistical methods for detecting and quantifying their effects are sorely needed. We present a collapsed double heterozygosity (CDH) test to detect the presence of multiple LOF alleles at a gene. When causal SNPs are available, which may be the case in next generation genome sequencing studies, this CDH test has overwhelmingly higher power than single SNP analysis. When causal SNPs are not directly available such as in current GWA settings, we show the CDH test has higher power than standard single SNP analysis if tagging SNPs are in linkage disequilibrium with the underlying causal SNPs to at least a moderate degree (r2>0.1). The test is implemented for genome-wide analysis in the publically available software package GenABEL which is based on a sliding window approach. We provide the proof of principle by conducting a genome-wide CDH analysis of red hair color, a trait known to be influenced by multiple loss-of-function alleles, in a total of 7,732 Dutch individuals with hair color ascertained. The association signals at the MC1R gene locus from CDH were uniformly more significant than traditional GWA analyses (the most significant P for CDH = 3.11×10-142vs. P for rs258322 = 1.33×10-66). The CDH test will contribute towards finding rare LOF variants in GWAS and sequencing studies.

Genetic determination of human facial morphology: Links between cleft-lips and normal variation (Article)

2011-11-01T00:00:00Z

Recent genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with non-syndromic cleft lip with or without cleft palate (NSCL/P), and other previous studies showed distinctly differing facial distance measurements when comparing unaffected relatives of NSCL/P patients with normal controls. Here, we test the hypothesis that genetic loci involved in NSCL/P also influence normal variation in facial morphology. We tested 11 SNPs from 10 genomic regions previously showing replicated evidence of association with NSCL/P for association with normal variation of nose width and bizygomatic distance in two cohorts from Germany (N=529) and the Netherlands (N=2497). The two most significant associations found were between nose width and SNP rs1258763 near the GREM1 gene in the German cohort (P=6 × 10 4), and between bizygomatic distance and SNP rs987525 at 8q24.21 near the CCDC26 gene (P=0.017) in the Dutch sample. A genetic prediction model explained 2% of phenotype variation in nose width in the German and 0.5% of bizygomatic distance variation in the Dutch cohort. Although preliminary, our data provide a first link between genetic loci involved in a pathological facial trait such as NSCL/P and variation of normal facial morphology. Moreover, we present a first approach for understanding the genetic basis of human facial appearance, a highly intriguing trait with implications on clinical practice, clinical genetics, forensic intelligence, social interactions and personal identity.

Postnatal parental smoking: An important risk factor for SIDS (Article)

2011-10-01T00:00:00Z

Background: Sudden infant death syndrome (SIDS) is the unexpected death of an infant that remains unexplained after a thorough investigation of the circumstances, family history, paediatric investigation and complete autopsy. In Western society, it is the leading cause of post-neonatal death below 1 year of age. In the Netherlands, the SIDS incidence is very low, which offers opportunities to assess the importance of old and new environmental risk factors. For this purpose, cases were collected through pathology departments and the working group on SIDS of the Dutch Paediatrician Foundation. A total of 142 cases were included; these occurred after the parental education on sleeping position (1987), restricted to the international age criteria and had no histological explanation. Age-matched healthy controls (N∈=∈2,841) came from a survey of the Netherlands Paediatric Surveillance Unit, completed between November 2002 and April 2003. A multivariate analysis was performed to determine the risk factors for SIDS, including sleeping position, antenatal maternal smoking, postnatal parental smoking, premature birth, gender, lack of breastfeeding and socio-economic status. Postnatal smoking was identified as an important environmental risk factor for SIDS (OR one parent∈=∈2.5 [1.2, 5.0]; both parents∈=∈5.77 [2.2, 15.5]; maternal∈=∈2.7 [1.0, 6.4]; paternal∈=∈2.4 [1.3, 4.5] ) as was prone sleeping (OR put prone to sleep∈=∈21.5 [10.6, 43.5]; turned prone during sleep∈=∈100 [46, 219]). Premature birth was also significantly associated with SIDS (OR∈=∈2.4 [1.2, 4.8]). Conclusion: Postnatal parental smoking is currently a major environmental risk factor for SIDS in the Netherlands together with the long-established risk of prone sleeping.

DNA-based eye colour prediction across Europe with the IrisPlex system (Article)

2011-08-02T00:00:00Z

The ability to predict Externally Visible Characteristics (EVCs) from DNA, also referred to as Forensic DNA Phenotyping (FDP), is an exciting new chapter in forensic genetics holding great promise for tracing unknown individuals who are unidentifiable via standard forensic short tandem repeat (STR) profiling. For the purpose of DNA-based eye colour prediction, we previously developed the IrisPlex system consisting of a multiplex genotyping assay and a prediction model based on genotype and phenotype data from 3804 Dutch Europeans. Recently, we performed a forensic developmental validation study of the highly sensitive IrisPlex assay, which currently represents the only validated tool available for DNA-based prediction of eye colour in forensic applications. In the present study, we validate the IrisPlex prediction model by extending our initially described model towards genotype and phenotype data from multiple European populations. We performed IrisPlex analysis on 3840 individuals from seven sites across Europe as part of the European Eye (EUREYE) study for which DNA and high-resolution eye images were available. The accuracy rate of correctly predicting an individual's eye colour as being blue or brown, above the empirically established probability threshold of 0.7, was on average 94% across all seven European populations, ranging from 91% to 98%, despite the large variation in eye colour frequencies between the populations. The overall prediction accuracies expressed by the area under the receiver characteristic operating curves (AUC) were 0.96 for blue and 0.96 for brown eyes, which is considerably higher than those established before. The IrisPlex prediction model parameters generated from this multi-population European dataset, and thus its prediction capabilities, were highly comparable to those previously established. Therefore, the increased information regarding eye colour phenotype and genotype distributions across Europe, and the system's ability to provide eye colour predictions across Europe accurately, both highlight additional evidence for the utility of the IrisPlex system in forensic casework.

Association of HSP70 and its co-chaperones with Alzheimer's disease (Article)

2011-07-01T00:00:00Z

The heat shock protein (HSP) 70 family has been implicated in the pathology of Alzheimer's disease (AD). In this study, we examined common genetic variations in the 80 genes encoding HSP70 and its co-chaperones. We conducted a study in a series of 462 patients and 5238 unaffected participants derived from the Rotterdam Study, a population-based study including 7983 persons aged 55 years and older. We genotyped a total of 12,053 Single Nucleotide Polymorphisms (SNPs) using the HumanHap550K Genotyping BeadChip from Illumina. Replication was performed in two independent cohort studies, the Framingham Heart study (FHS; n = 806) and Cardiovascular Health Study (CHS; n = 2150). When adjusting for multiple testing, we found a small but consistent, though not significant effect of rs12118313 located 32 kb from PFDN2, with an OR of 1.19 (p-value from meta-analysis = 0.003). However this SNP was in the intron of another gene, suggesting it is unlikely this SNP reflects the effect of PFDN2. In a formal pathway analysis we found nominally significant evidence for an association of BAG, DNAJA and prefoldin with AD. These findings corroborate with those of a study of 2032 AD patients and 5328 controls, in which several members of the prefoldin family showed evidence for association to AD. Our study did not reveal evidence for a genetic variant if the HSP70 family with a major effect on AD. However, our findings of the single SNP analysis and pathway analysis suggest that multiple genetic variants in prefoldin are associated with AD.

IrisPlex: A sensitive DNA tool for accurate prediction of blue and brown eye colour in the absence of ancestry information (Article)

2011-06-01T00:00:00Z

A new era of 'DNA intelligence' is arriving in forensic biology, due to the impending ability to predict externally visible characteristics (EVCs) from biological material such as those found at crime scenes. EVC prediction from forensic samples, or from body parts, is expected to help concentrate police investigations towards finding unknown individuals, at times when conventional DNA profiling fails to provide informative leads. Here we present a robust and sensitive tool, termed IrisPlex, for the accurate prediction of blue and brown eye colour from DNA in future forensic applications. We used the six currently most eye colour-informative single nucleotide polymorphisms (SNPs) that previously revealed prevalence-adjusted prediction accuracies of over 90% for blue and brown eye colour in 6168 Dutch Europeans. The single multiplex assay, based on SNaPshot chemistry and capillary electrophoresis, both widely used in forensic laboratories, displays high levels of genotyping sensitivity with complete profiles generated from as little as 31 pg of DNA, approximately six human diploid cell equivalents. We also present a prediction model to correctly classify an individual's eye colour, via probability estimation solely based on DNA data, and illustrate the accuracy of the developed prediction test on 40 individuals from various geographic origins. Moreover, we obtained insights into the worldwide allele distribution of these six SNPs using the HGDP-CEPH samples of 51 populations. Eye colour prediction analyses from HGDP-CEPH samples provide evidence that the test and model presented here perform reliably without prior ancestry information, although future worldwide genotype and phenotype data shall confirm this notion. As our IrisPlex eye colour prediction test is capable of immediate implementation in forensic casework, it represents one of the first steps forward in the creation of a fully individualised EVC prediction system for future use in forensic DNA intelligence.

Model-based prediction of human hair color using DNA variants (Article)

2011-04-01T00:00:00Z

Predicting complex human phenotypes from genotypes is the central concept of widely advocated personalized medicine, but so far has rarely led to high accuracies limiting practical applications. One notable exception, although less relevant for medical but important for forensic purposes, is human eye color, for which it has been recently demonstrated that highly accurate prediction is feasible from a small number of DNA variants. Here, we demonstrate that human hair color is predictable from DNA variants with similarly high accuracies. We analyzed in Polish Europeans with single-observer hair color grading 45 single nucleotide polymorphisms (SNPs) from 12 genes previously associated with human hair color variation. We found that a model based on a subset of 13 single or compound genetic markers from 11 genes predicted red hair color with over 0.9, black hair color with almost 0.9, as well as blond, and brown hair color with over 0.8 prevalence-adjusted accuracy expressed by the area under the receiver characteristic operating curves (AUC). The identified genetic predictors also differentiate reasonably well between similar hair colors, such as between red and blond-red, as well as between blond and dark-blond, highlighting the value of the identified DNA variants for accurate hair color prediction.

Estimating human age from T-cell DNA rearrangements (Article)

2010-11-23T00:00:00Z

Predicting human phenotypes from genotypes is a newly emerging field with relevance for personalized medicine [1] and forensics [2]. However, only a few phenotypic traits can currently be identified from DNA information with accuracies sufficient for practical applications [1], most notably human eye (iris) color [3]. It could be expected that individual age is too biologically complex to allow a simple and accurate molecular estimation from biological materials. Indeed, previously proposed genetic methods for human age estimation, based on the accumulation of mitochondrial DNA deletions or on telomere shortening, show low accuracies and various technical problems, and are therefore not suitable for practical applications [4]. Proposed biochemical methods, such as those based on the accumulation of D-aspartic acid, involve the destructive analysis of specific body parts (such as bones, teeth and ligaments), and suffer from technical issues and bio-degradation [4]. In the present study, we demonstrate that human individual age can be estimated accurately and reliably from blood using T-cell DNA rearrangements, and we provide a robust and sensitive real-time quantitative PCR protocol for application in various areas of bioscience.

Digital quantification of human eye color highlights genetic association of three new loci. (Article)

2010-09-07T00:00:00Z

Previous studies have successfully identified genetic variants in several genes associated with human iris (eye) color; however, they all used simplified categorical trait information. Here, we quantified continuous eye color variation into hue and saturation values using high-resolution digital full-eye photographs and conducted a genome-wide association study on 5,951 Dutch Europeans from the Rotterdam Study. Three new regions, 1q42.3, 17q25.3, and 21q22.13, were highlighted meeting the criterion for genome-wide statistically significant association. The latter two loci were replicated in 2,261 individuals from the UK and in 1,282 from Australia. The LYST gene at 1q42.3 and the DSCR9 gene at 21q22.13 serve as promising functional candidates. A model for predicting quantitative eye colors explained over 50% of trait variance in the Rotterdam Study. Over all our data exemplify that fine phenotyping is a useful strategy for finding genes involved in human complex traits.

A Genome-Wide Screen for Depression in Two Independent Dutch Populations (Article)

2010-07-15T00:00:00Z

Background: Depression has a strong genetic component but candidate gene studies conducted to date have not shown consistent associations. Methods: We conducted a genome-wide parametric and nonparametric linkage analysis in a large-scale family-based study including 115 individuals with depression who were identified based on the Hospital Anxiety Depression Scale, Center for Epidemiologic Studies Depression Rating Scale, or use of antidepressive medication. Further, we investigated the most promising chromosomal regions found in the genome-wide linkage analysis with an association analysis in 734 individuals in the family-based study and 2373 individuals in the population-based study. Results: Our study demonstrated evidence for significant linkage of depression to chromosome 2p16.1-15 (logarithm of odds [LOD] = 5.13; parametric analysis) and suggestive evidence for linkage in nonparametric analysis to chromosome 5p15.33 (LOD = 2.14), 11q25 (LOD = 2.27), and 19p13.3 (LOD = 2.66). The subsequent association analysis in the family-based study showed region-wide significant association in intron 1 of the OPCML gene on chromosome 11q25 (empirical p value = .04). The association analysis in the population-based study did not show any region-wide significant association, yet showed suggestive association in intron 1 of the APLP2 gene on chromosome 11q25. Conclusions: Our linkage and association studies suggest a locus for depression on chromosomes 2p16.1-15 and 11q25. The linkage to chromosome 11q25 may be, in part, explained by the OPCML or the APLP2 gene. Further, there is evidence for a role of the GNG7 gene (chromosome 19p13.3).

A study of the SORL1 Gene in Alzheimer's disease and cognitive function (Article)

2009-09-21T00:00:00Z

Several studies have investigated the role of the neuronal sortilin-related receptor (SORL1) gene in Alzheimer's disease (AD), but findings have been inconsistent. We conducted a study of 7 single nucleotide polymorphisms (SNPs), rs668387, rs689021, rs641120, rs1699102, rs3824968, rs2282649, and rs1010159, in the SORL1 gene that were associated to AD in previous studies. We tested for association with AD and cognitive function in 6741 participants of the Rotterdam Study and in 2883 individuals from the Erasmus Rucphen Family study. We performed meta-analyses on AD using our data together with those of previous studies published prior to September 2008 in Caucasians. Further, we studied up to 76 SNPs in a 400 kb region within and flanking the gene to evaluate the evidence that other genetic variants are associated with AD or cognitive function. There was no significant evidence for association between SORL1 SNPs and incident AD patients in the Rotterdam Study. In a meta-analysis of our data with those of others, six out of seven SNPs attained borderline significance. However, removal of the first study reporting association from the meta-analysis resulted in non-significant odds ratios for all SNPs. SNPs rs668387, rs689021, and rs641120 were associated with cognitive function in non-demented individuals at borderline statistical significance in two independent Dutch cohorts, but in the opposite direction. Testing for association using dense SNPs in the SORL1 gene did not reveal significant association with AD, or with cognitive function when adjusting for multiple testing. In conclusion, our data do not support the hypothesis that genetic variants in SORL1 are related to the risk of AD.

A genome-wide association study of northwestern Europeans involves the C-type natriuretic peptide signaling pathway in the etiology of human height variation (Article)

2009-09-04T00:00:00Z

Northwestern Europeans are among the tallest of human populations. The increase in body height in these people appears to have reached a plateau, suggesting the ubiquitous presence of an optimal environment in which genetic factors may have exerted a particularly strong influence on human growth. Therefore, we performed a genome-wide association study (GWAS) of body height using 2.2 million markers in 10 074 individuals from three Dutch and one German population-based cohorts. Upon genotyping, the 12 most significantly height-associated single nucleotide polymorphisms (SNPs) from this GWAS in 6912 additional individuals of Dutch and Swedish origin, a genetic variant (rs6717918) on chromosome 2q37.1 was found to be associated with height at a genome-wide significance level (Pcombined= 3.4 × 10-9). Notably, a second SNP (rs6718438) located ∼450 bp away and in strong LD (r2= 0.77) with rs6717918 was previously found to be suggestive of a height association in 29 820 individuals of mainly northwestern European ancestry, and the over-expression of a nearby natriuretic peptide precursor type C (NPPC) gene, has been associated with overgrowth and skeletal anomalies. We also found a SNP (rs10472828) located on 5p14 near the natriuretic peptide receptor 3 (NPR3) gene, encoding a receptor of the NPPC ligand, to be associated with body height (Pcombined= 2.1 × 10-7). Taken together, these results suggest that variation in the C-type natriuretic peptide signaling pathway, involving the NPPC and NPR3 genes, plays an important role in determining human body height.

The GAB2 Gene and the Risk of Alzheimer's Disease: Replication and Meta-Analysis (Article)

2009-06-01T00:00:00Z

Background: Recently, GAB2 has been suggested to modify the risk of late-onset Alzheimer's disease (AD) among APOEε4 carriers. However, replication data are inconsistent. Methods: In a population-based cohort study (n = 5507; age > 55) with 443 incident AD cases, we investigated the association between rs4945261 and AD. Because we used high-density genotyping, we also investigated other polymorphisms within and around GAB2 and performed a meta-analysis with published studies. Results: We found that rs4945261 was associated with AD among APOEε4 carriers (p = .02) but not among noncarriers (p = .26). Fifteen of the 20 remaining polymorphisms within GAB2 and several polymorphisms in the 250kbp-region surrounding GAB2 were also associated with AD among carriers and only one among noncarriers. For rs2373115, meta-analysis yielded an odds ratio of 1.58 (1.17-2.14) with p = 3.0 * 10-3among carriers and 1.09 (.97-1.23) with p = .16 among noncarriers. For rs4945261, the pooled odds ratio was 1.75 (1.21-2.55) with p = 3.0 * 10-3among carriers and 1.20 (1.01-1.41) with p = .03 among noncarriers. Conclusions: We found GAB2 to be associated with AD. Furthermore, the meta-analysis also suggests that GAB2 modifies the risk of AD in APOEε4 carriers.

Eye color and the prediction of complex phenotypes from genotypes (Article)

2009-03-10T00:00:00Z

Predicting complex human phenotypes from genotypes has recently gained tremendous interest in the emerging field of consumer genomics, particularly in light of attempting personalized medicine [1,2]. So far, however, this approach has not been shown to be accurate, thus limiting its practical applications [3,4]. Here, we used human eye (iris) color of Europeans as an empirical example to demonstrate that highly accurate genetic prediction of complex human phenotypes is feasible. Moreover, the six DNA markers we identified as major eye color predictors will be valuable in forensic studies.

Methodological Approaches to Study the Genetics of Dementia and Cognitive Function (Doctoral Thesis)

2009-02-18T00:00:00Z

Alzheimer’s disease (AD) is the main cause of dementia and one of the most burdensome conditions of later life. The prevalence of AD grows exponentially with age, starting at less than 1% at the age of 60 years, reaching as high as 33% at the age of 85 years1. Smoking is one of the few non-genetic risk factors known to be involved in AD. Family history of AD has long been known as a strong predictor of the disease and the heritability of the disease was estimated as high as 79%2. Several genetic factors involved in AD have been identifi ed since the end of last century. These include the amyloid precursor protein gene (APP), the Presenilin 1 gene (PSEN1) and the Presenilin 2 gene (PSEN2), which are involved in early onset AD. Mutations in APP cause excessive cleavage by the β- and γ-secretase enzymes, instead of normal cleavage by the α-secretase enzyme. The result is an increased production of toxic β-amyloid fragments, which are converted into insoluble aggregates that form senile plaques in brain tissue. PSEN1 and PSEN2 are involved in the γ-secretase complex, and mutations lead to excessive cleavage by the γ-secretes enzyme, which results in increased production and accumulation of β-amyloid fragments. To date, no monogenic mutation was described for late-onset AD. The genetic factor, which is most predominant in both early and late onset AD, is the apolipoprotein E gene (APOE). The APOE gene has 3 common allelic forms, E2 (which occurs with a frequency about 8% in Europeans), E3 (about 75%), and E4 (about 15%). The E4 allele is associated with an increased risk of AD. Compared to non-carriers, the carriers of a single copy of the E4 allele have a 3-4 fold increased risk to develop AD, and the carriers of two copies of the E4 allele have a 10-12 fold increased risk to develop AD. APOE is involved in cholesterol transport and β-amyloid formation3, but the exact mechanism how it promotes AD remains unclear. Recently, a genetic test for APOE genotype was marketed as a tool for predicting the risk of AD (http://www.labtestsonline.org).

The MSX1 allele 4 homozygous child exposed to smoking at periconception is most sensitive in developing nonsyndromic orofacial clefts (Article)

2008-10-20T00:00:00Z

Nonsyndromic orofacial clefts (OFC) are common birth defects caused by certain genes interacting with environmental factors. Mutations and association studies indicate that the homeobox gene MSX1 plays a role in human clefting. In a Dutch case-control triad study (mother, father, and child), we investigated interactions between MSX1 and the parents' periconceptional lifestyle in relation to the risk of OFC in their offspring. We studied 181 case- and 132 control mothers, 155 case- and 121 control fathers, and 176 case- and 146 control children, in which there were 107 case triads and 66 control triads. Univariable and multivariable logistic regression analyses were applied, and odds ratios (OR), 95% confidence intervals (CI) were calculated. Allele 4 of the CA marker in the MSX1 gene, consisting of nine CA repeats, was the most common allele found in both the case and control triads. Significant interactions were observed between allele 4 homozygosity of the child with maternal smoking (OR 2.7, 95% CI 1.1-6.6) and with smoking by both parents (OR 4.9, 95% CI 1.4-18.0). Allele 4 homozygosity in the mother and smoking showed a risk estimate of OR 3.2 (95% CI 1.1-9.0). If allele 4 homozygous mothers did not take daily folic acid supplements in the recommended periconceptional period, this also increased the risk of OFC for their offspring (OR 2.8, 95% CI 1.1-6.7). Our findings show that, in the Dutch population, periconceptional smoking by both parents interacts with a specific allelic variant of MSX1 to significantly increase OFC risk for their offspring. Possible underlying mechanisms are discussed.

Familial aggregation of preeclampsia and intrauterine growth restriction in a genetically isolated population in The Netherlands (Article)

2008-07-10T00:00:00Z

Preeclampsia and intrauterine growth restriction are related, pregnancy-specific disorders with a substantial genetic influence, which may have a joint genetic aetiology. We investigated familial aggregation, consanguinity and parent-of-origin effects for preeclampsia and IUGR. Fifty women with previous preeclampsia and 56 with previous pregnancies complicated by intrauterine growth restriction were recruited from a recent genetically isolated population in the Netherlands. Their relationships were estimated by means of a large genealogy database that contains information on more than 110000 individuals from the isolate over 23 generations. Relationships were quantified using kinship and inbreeding coefficients. Parent-of-origin effects were evaluated by comparing parental kinships. Eighty-six women (39 preeclampsia and 47 intrauterine growth restriction) could be linked to one common ancestor within 14 generations. The proportion of related women with previous preeclampsia (95.6%) or pregnancies complicated by intrauterine growth restriction (95.1%) was significantly greater than expected by chance (P<0.001). Combined analysis of both disorders did not change the magnitude of familial aggregation. The proportion of women born from consanguineous marriages was increased in women with previous preeclampsia (81.8%) and those with intrauterine growth restriction (78%) compared to a random sample (P<0.001). Maternal and paternal kinships were not significantly different in both disorders. We demonstrate cosegregation of preeclampsia and intrauterine growth restriction, supporting a common genetic aetiology. The high proportion of parental consanguineous marriages suggests the possibility of an underlying recessive mutation. No evidence was found for a parent-of-origin effect either in preeclampsia or in intrauterine growth restriction.

An approach for cutting large and complex pedigrees for linkage analysis (Article)

2008-07-01T00:00:00Z

Utilizing large pedigrees in linkage analysis is a computationally challenging task. The pedigree size limits applicability of the Lander-Green-Kruglyak algorithm for linkage analysis. A common solution is to split large pedigrees into smaller computable subunits. We present a pedigree-splitting method that, within a user supplied bit-size limit, identifies subpedigrees having the maximal number of subjects of interest (eg patients) who share a common ancestor. We compare our method with the maximum clique partitioning method using a large and complex human pedigree consisting of 50 patients with Alzheimer's disease ascertained from genetically isolated Dutch population. We show that under a bit-size limit our method can assign more patients to subpedigrees than the clique partitioning method, particularly when splitting deep pedigrees where the subjects of interest are scattered in recent generations and are relatively distantly related via multiple genealogic connections. Our pedigree-splitting algorithm and associated software can facilitate genome-wide linkage scans searching for rare mutations in large pedigrees coming from genetically isolated populations. The software package PedCut implementing our approach is available at http://mga.bionet.nsc.ru/soft/index.html.

Maternal transmission of multiple sclerosis in a Dutch population (Article)

2008-03-01T00:00:00Z

Objective: To investigate the parental relationship of patients with multiple sclerosis (MS) from an extended pedigree with extensive genealogical information up to the middle of the 18th century. Design: Multiple sclerosis is a complex disease resulting from genetic and environmental factors. Parent-of-origin effect, a phenomenon when the same allele may express differently depending on the sex of the transmitting parent, may influence the risk for MS. We investigated parental relationships between patients with MS using extensive genealogical information available from the Genetic Research in Isolated Populations program. We compared the average kinship of the parents of MS patients. We further explored the distribution of shortest genealogical links between parents of MS patients. Subjects: Twenty-four MS patients from the isolated population who could be linked within a large complex pedigree, including 2471 people in total. Results: The results consistently indicate a higher prevalence of maternal transmission of MS. The kinship between mothers of patients was 3.8 times higher than that between fathers (bootstrap P=.01). Among the 814 shortest connections between parents, 333 were maternal (40.9%, vs 25.0% expected), 98 were paternal (12.0%, vs 25.0% expected), and 383 were maternal-paternal (47.1%, vs 50.0% expected) (P<.001). Conclusions: Mothers of MS patients were more closely related than their fathers. This skewed relationship shows evidence for a maternal effect in MS. The most likely explanation is a gene-environment effect that takes place in utero.

Three Genome-wide Association Studies and a Linkage Analysis Identify HERC2 as a Human Iris Color Gene (Article)

2008-02-08T00:00:00Z

Human iris color was one of the first traits for which Mendelian segregation was established. To date, the genetics of iris color is still not fully understood and is of interest, particularly in view of forensic applications. In three independent genome-wide association (GWA) studies of a total of 1406 persons and a genome-wide linkage study of 1292 relatives, all from the Netherlands, we found that the 15q13.1 region is the predominant region involved in human iris color. There were no other regions showing consistent genome-wide evidence for association and linkage to iris color. Single nucleotide polymorphisms (SNPs) in the HERC2 gene and, to a lesser extent, in the neighboring OCA2 gene were independently associated to iris color variation. OCA2 has been implicated in iris color previously. A replication study within two populations confirmed that the HERC2 gene is a new and significant determinant of human iris color variation, in addition to OCA2. Furthermore, HERC2 rs916977 showed a clinal allele distribution across 23 European populations, which was significantly correlated to iris color variation. We suggest that genetic variants regulating expression of the OCA2 gene exist in the HERC2 gene or, alternatively, within the 11.7 kb of sequence between OCA2 and HERC2, and that most iris color variation in Europeans is explained by those two genes. Testing markers in the HERC2-OCA2 region may be useful in forensic applications to predict eye color phenotypes of unknown persons of European genetic origin.

The apolipoprotein E gene and its age-specific effects on cognitive function (Article)

2008-01-01T00:00:00Z

The E4 allele of the apolipoprotein E gene (APOE) is a well-established determinant of Alzheimer's disease but its relation to cognitive function is much less understood. We studied the age-specific effects of the APOE*E4 allele on cognitive function and cardiovascular risk factors in 2208 related individuals. APOE*E4 allele was significantly associated with reduced test scores for Adult Verbal Learning Test, particularly on the memory and learning sub domains, in persons older than 50 years of age. The effect of APOE*E4 was independent of the effect of APOE*E4 on vascular risk factors and most pronounced on learning ability. Our findings suggest that APOE*E4 has an effect on cognitive function predominantly in the elderly, independent of vascular risk factors.

Breaking loops in large complex pedigrees (Article)

2007-11-01T00:00:00Z

For pedigrees with multiple loops, exact likelihoods could not be computed in an acceptable time frame and thus, approximate methods are used. Some of these methods are based on breaking loops and approximations of complex pedigree likelihoods using the exact likelihood of the corresponding zero-loop pedigree. Due to ignoring loops, this method results in a loss of genetic information and a decrease in the power to detect linkage. To minimize this loss, an optimal set of loop breakers has to be selected. In this paper, we present a graph theory based algorithm for automatic selection of an optimal set of loop breakers. We propose using a total relationship between measured pedigree members as a proxy to power. To minimize the loss of genetic information, we suggest selection of such breakers whose duplication in a pedigree would be accompanied by a minimal loss of total relationship between measured pedigree members. We show that our algorithm compares favorably with other existing loop-breaker selection algorithms in terms of conservation of genetic information, statistical power and CPU time of subsequent linkage analysis. We implemented our method in a software package LOOP_EDGE, which is available at http://mga.bionet.nsc.ru/nlru/. Copyright

Relationship of the Ubiquilin 1 gene with Alzheimer's and Parkinson's disease and cognitive function (Article)

2007-08-31T00:00:00Z

Ubiquilin 1 (UBQLN1) is involved in the ubiquitination machinery, which has been implicated in Alzheimer's disease (AD) as well as Parkinson's disease (PD). A polymorphism in the gene encoding for UBQLN1 has been previously associated with a higher risk of AD. We studied the role of the SNP rs12344615 on the UBQLN 1 gene in AD, PD and cognitive function in a population-based study, the Rotterdam Study, and a family-based study embedded in the genetic research in isolated population (GRIP) program. The Rotterdam Study includes 549 patients with AD and 157 patients with PD. The GRIP program includes a series of 123 patients with AD and a study of 1049 persons who are characterized for cognitive function. Data were analysed using logistic and multiple regression analysis. We found no significant difference in risk of AD or PD by the UBQLN1 SNP rs12344615 in our overall and stratified analyses in the Rotterdam Study. In our family-based study, we did not find evidence for linkage of AD to the region including the UBQLN1 gene. In the family-based study we also failed to detect an effect of this polymorphism on cognitive function. Our results suggest that it is unlikely that the SNP rs12344615 of the UBQLN1 gene is related to the onset of AD, PD or cognitive function.

A genomewide screen for late-onset Alzheimer disease in a genetically isolated Dutch population (Article)

2007-07-01T00:00:00Z

Alzheimer disease (AD) is the most common cause of dementia. We conducted a genome screen of 103 patients with late-onset AD who were ascertained as part of the Genetic Research in Isolated Populations (GRIP) program that is conducted in a recently isolated population from the southwestern area of The Netherlands. All patients and their 170 closely related relatives were genotyped using 402 microsatellite markers. Extensive genealogy information was collected, which resulted in an extremely large and complex pedigree of 4,645 members. The pedigree was split into 35 subpedigrees, to reduce the computational burden of linkage analysis. Simulations aiming to evaluate the effect of pedigree splitting on false-positive probabilities showed that a LOD score of 3.64 corresponds to 5% genomewide type I error. Multipoint analysis revealed four significant and one suggestive linkage peaks. The strongest evidence of linkage was found for chromosome 1q21 (heterogeneity LOD [HLOD] = 5.20 at marker D1S498). Approximately 30 cM upstream of this locus, we found another peak at 1q25 (HLOD = 4.0 at marker D1S218). These two loci are in a previously established linkage region. We also confirmed the AD locus at 10q22-24 (HLOD = 4.15 at marker D10S185). There was significant evidence of linkage of AD to chromosome 3q22-24 (HLOD = 4.44 at marker D3S1569). For chromosome 11q24-25, there was suggestive evidence of linkage (HLOD = 3.29 at marker DI1S1320). We next tested for association between cognitive function and 4,173 single-nucleotide polymorphisms in the linked regions in an independent sample consisting of 197 individuals from the GRIP region. After adjusting for multiple testing, we were able to detect significant associations for cognitive function in four of five AD-linked regions, including the new region on chromosome 3q22-24 and regions 1q25, 10q22-24, and 11q25. With use of cognitive function as an endophenotype of AD, our study indicates the that the RGSL2, RALGPS2, and C1orf49 genes are the potential disease-causing genes at 1q25. Our analysis of chromosome 10q22-24 points to the HTR7, MPHOSPH1, and CYP2C cluster. This is the first genomewide screen that showed significant linkage to chromosome 3q23 markers. For this region, our analysis identified the NMNAT3 and CLSTN2 genes. Our findings confirm linkage to chromosome 11q25. We were unable to confirm SORLI; instead, our analysis points to the OPCML and HNT genes.

IGF-1 CA repeat variant and breast cancer risk in postmenopausal women (Article)

2007-07-01T00:00:00Z

IGF-I is an important growth factor for the mammary gland. We evaluated the relationship of the IGF-I CAnpolymorphism with breast cancer risk in Caucasian postmenopausal women and performed a meta-analysis of published data. The IGF-I CAnpolymorphism was genotyped in 4091 from the Rotterdam Study. A disease-free survival analysis was performed along with a meta-analysis of all available data on IGF-I CAnpolymorphism and breast cancer risk. During follow-up 159 women were diagnosed with breast cancer. The disease-free survival analysis adjusted for age at entry, age at menopause, body mass index and waist hip ratio yielded a HR = 0.97 (95% CI=0.59-1.58) for CA19non-carriers against carriers. The meta-analysis using the random-effects model gave a pooled OR of 1.26 (95% CI = 0.95-1.82) for IGF-I CA19non-carriers versus CA19homozygous carriers. According to these results, the IGF-I CA19promoter polymorphism is not likely to predict the risk of breast cancer.