Identification of two novel quantitative trait loci for pre-eclampsia susceptibility on chromosomes 5q and 13q using a variance components-based linkage approach

Pre-eclampsia/eclampsia (PE/E) is a common and serious disorder of human pregnancy that is associated with substantial maternal and perinatal morbidity and mortality. The suspected aetiology of PE/E is complex, with susceptibility being attributable to multiple environmental factors and a large genetic component. By assuming that the underlying liability towards PE/E susceptibility is inherently quantitative, any PE/E susceptibility gene would represent a quantitative trait locus (QTL). This assumption enables a more refined and powerful variance components procedure using a threshold model for our PE/E statistical analysis. Using this more efficient linkage approach, we have now re-analysed our previously completed Australian/New Zealand genome scan data to identify two novel PE/E susceptibility QTLs on chromosomes 5q and 13q. We have obtained strong evidence of linkage on 5q with a peak logarithm-of-odds (LOD) score of 3.12 between D5S644 and D5S433 [at approximately 121 centimorgan (cM)] and strong evidence of linkage on 13q with a peak LOD score of 3.10 between D13S1265 and D13S173 (at approximately 123 cM). Objective identification and prioritization of positional candidate genes using the quantitative bioinformatics program GeneSniffer revealed highly plausible PE/E candidate genes encoding aminopeptidase enzymes and a placental peptide hormone on the 5q QTL and two type IV collagens on the 13q QTL regions, respectively.     

Mapping for dyslexia and related cognitive trait loci provides strong evidence for further risk genes on chromosome 6p21

In a genome‐wide linkage scan, we aimed at mapping risk loci for dyslexia in the German population. Our sample comprised 1,030 individuals from 246 dyslexia families which were recruited through a single‐proband sib pair study design and a detailed assessment of dyslexia and related cognitive traits. We found evidence for a major dyslexia locus on chromosome 6p21. The cognitive trait rapid naming (objects/colors) produced a genome‐wide significant LOD score of 5.87 (P = 1.00 × 10^?7) and the implicated 6p‐risk region spans around 10 Mb. Although our finding maps close to DYX2, where the dyslexia candidate genes DCDC2 and KIAA0319 have already been identified, our data point to the presence of an additional risk gene in this region and are highlighting the impact of 6p21 in dyslexia and related cognitive traits. © 2010 Wiley‐Liss, Inc.     

Follow-up study on a susceptibility locus for schizophrenia on chromosome 6q

Evidence for suggestive linkage to schizophrenia with chromosome 6q markers was previously reported from a two-stage approach. Using nonparametric affected sib pairs (ASP) methods, nominal p-values of 0.00018 and 0.00095 were obtained in the screening (81 ASPs; 63 independent) and the replication (109 ASPs; 87 independent) data sets, respectively. Here, we report a follow-up study of this 50cM 6q region using 12 microsatellite markers to test for linkage to schizophrenia. We increased the replication sample size by adding an independent sample of 43 multiplex pedigrees (66 ASPs; 54 independent). Pairwise and multipoint nonparametric linkage analyses conducted in this third data set showed evidence consistent with excess sharing in this 6q region, though the statistical level is weaker (p=0.013). When combining both replication data sets (total of 141 independent ASPs), an overall nominal p-value=0.000014 (LOD=3.82) was obtained. The sibling recurrence risk (λs) attributed to this putative 6q susceptibility locus is estimated to be 1.92. The linkage region could not be narrowed down since LOD score values greater than three were observed within a 13cM region. The length of this region was only slightly reduced (12cM) when using the total sample of independent ASPs (204) obtained from all three data sets. This suggests that very large sample sizes may be needed to narrow down this region by ASP linkage methods. Study of the etiological candidate genes in this region is ongoing. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:337–343, 1999. © 1999 Wiley-Liss, Inc.     

Fine mapping supports previous linkage evidence for a bipolar disorder susceptibility locus on 13q32

A region between D13S71 and D13S274 on 13q32 showed linkage to bipolar disorder (BP) based on a genome scan using markers with an average spacing of approximately 6 cM and an average heterozygosity of approximately 60% [Detera-Wadleigh et al., 1999: Proc Natl Acad Sci USA 96:5604-5609]. In an attempt to confirm this finding and achieve fine mapping of the susceptibility region, nine additional microsatellite markers with average heterozygosity of approximately 86%, located between D13S71 and D13S274, were typed in the same sample. The strongest linkage evidence was detected by multipoint linkage analysis (ASPEX program) around D13S779-D13S225 with maximum LOD score of 3.25 under Affection Status Model II (ASM II; P = 0.0000546). Data from additional nine markers resulted in a decrease of the 95% confidence interval of the linkage region. Association analyses with GASSOC TDT and ASPEX/sib_tdt detect potential linkage disequilibrium with several markers, including D13S280 (ASPEX TDT P = 0.0033, ASM I). These data generated using a higher marker density within the proposed susceptibility region strengthen the validity of our previous findings and suggest a finer localization of the susceptibility gene(s) on 13q32.     

Initial Genome Scan of the NIMH Genetics Initiative Bipolar Pedigrees: Chromosomes 4, 7, 9, 18, 19, 20, and 21q

An initial genome scan was performed on 540 individuals from 97 families segregating bipolar disorder, collected through the National Institutes of Mental Health Genetics Initiative. We report here affected-sib-pair (ASP) data on 126 marker loci (≈68,000 genotypes) mapping to chromosomes 4, 7, 9, 18, 19, 20, and 21q, under three affection status models. Modest increases in identical-by-descent (IBD) allele sharing were found at the following loci: D4S2397 and D4S391 ( P < 0.05) on 4p, D4S1647 ( P < 0.05) on 4q, D7S1802 and D7S1869 (low P = 0.01) on 7p, D9S302 ( P = 0.004) on 9q, and D20S604 on 20p and D20S173 on 20q ( P ≤ 0.05). In addition, five markers on 7q displayed increased IBD sharing ( P = 0.046–0.002). Additional ASP analyses on chromosomes 18 and 21q marker data were performed using disease phenotype models defined previously. On chromosome 18, only D18S40 on 18p and D18S70 on 18q yielded a slight elevation in allele sharing ( P = 0.02), implying that the reported linkages in these regions were not confirmed. On chromosome 21q, a cluster of markers within an ≈9 cM interval: D21S1254, D21S65, D21S1440, and D21S1255 exhibited excess allele sharing ( P = 0.041–0.008). Multilocus data on overlapping marker quartets, from D21S1265 to D21S1255, which were consistent with increased IBD sharing ( P < 0.01, with a low of 0.0009), overlapped a broad interval of excess allele sharing reported previously, increasing support for a susceptibility locus for bipolar disorder on 21q. Am. J. Med. Genet. 74:254–262, 1997. © 1997 Wiley-Liss, Inc.     

Fine‐mapping scan of bipolar disorder susceptibility loci in Latino pedigrees

We previously identified bipolar disorder (BD) susceptibility loci on 8q24, 14q32, and 2q12‐14 in a genome‐wide nonparametric linkage screen in a Latino cohort. We now perform a fine mapping analysis using a dense map of additional SNPs to identify BD susceptibility genes within these regions. One thousand nine hundred and thirty‐eight individuals with Latino ancestry (880 individuals with BD Type I or Schizoaffective, Bipolar Type) from 416 Latino pedigrees from the United States, Mexico, Costa Rica, and Guatemala were genotyped with 3,074 SNPs to provide dense coverage of the 8q24 (11.5 cM), 14q32 (7.5 cM), and 2q12‐14 (6.5 cM) chromosomal loci. Single‐marker association tests in the presence of linkage were performed using the LAMP software. The top linkage peak (rs7834818; LOD = 5.08, p = 3.30E ? 5) and associated single marker (rs2280915, p = 2.70E ? 12) were located within FBXO32 on 8q24. On chromosome 2, the top linkage peak (rs6750326; LOD = 5.06, p = 3.50E ? 5) and associated single marker (rs11887088, p = 2.90E ? 6) were located in intragenic regions near ACTR3 and DPP10. None of the additional markers in the region around chromosome 14q32 met significance levels for linkage or association. We identified six SNPs on 2q12‐q14 and one SNP in FBXO32 on 8q24 that were significantly associated with BD in this Latino cohort.     

A follow‐up linkage study supports evidence for a bipolar affective disorder locus on chromosome 21q22

Evidence for linkage between bipolar affective disorder (BP) and 21q22 was first reported by our group in a single large pedigree with a lod score of 3.41 with the PFKL locus. In a subsequent study, with denser marker coverage in 40 multiplex BP pedigrees, we reported supporting evidence with a two‐point lod score of 2.76 at the D21S1260 locus, about 6 cM proximal to PFKL. For cost‐efficiency, the individuals genotyped in that study comprised a subset of our large pedigree sample. To augment our previous analysis, we now report a follow‐up study including a larger sample set with an additional 331 typed individuals from the original 40 families, improved marker coverage, and an additional 16 pedigrees. The analysis of all 56 pedigrees (a total of 862 genotyped individuals vs. the 372 genotyped previously), the largest multigenerational BP pedigree sample reportedly analyzed to date, supports our previous results, with a two‐point lod score of 3.56 with D21S1260. The 16 new pedigrees analyzed separately gave a maximum two‐point lod score of 1.89 at D21S266, less than 1 cM proximal to D21S1260. Our results are consistent with a putative BP locus on 21q22. © 2001 Wiley‐Liss, Inc.     

Fine-scale mapping of type I allergy candidate loci suggests central susceptibility genes on chromosomes 3q, 4q and Xp

BACKGROUND: Type I allergy globally affects an increasing number of individuals with the consequence of considerable personal morbidity and socio-economic costs. Identification of disease susceptibility genes would render enormous medical perspectives in terms of improved diagnosis, treatment and prevention. Like for other complex disorders, achievement of the knowledge necessary depends on confirmation of reported genomic candidate regions. METHODS: We performed a two-stage fine-scale linkage analysis in 11 selected candidate regions on chromosome 3p, 3q, 4p, 4q, 5q, 6p, 9p, 12q, 12qter, 18q and Xp. We analysed 97 polymorphic markers in 424 individuals from 100 sib-pair families and evaluated the data for five phenotypes: Allergic asthma, atopic dermatitis, allergic rhinitis and total and specific immunoglobulin E. RESULTS: The highest maximum likelihood scores (MLS) were obtained on chromosomes 3q (MLS = 2.69), 4p (MLS = 2.34), 4q (MLS = 2.75), 6p (MLS = 2.22), 12qter (MLS = 2.15) and Xp (MLS = 2.23). All five phenotypes showed MLS >/= 2 in one or more of the candidate regions. CONCLUSIONS: Susceptibility genes in the 3q, 4q and Xp regions may play a central role in the inheritance of allergic disease, as positive results were obtained for all five phenotypes in these three regions.     

Analysis of thirteen trinucleotide repeat loci as candidate genes for schizophrenia and bipolar affective disorder

A group of diseases are due to abnormal expansions of trinucleotide repeats. These diseases all affect the nervous system. In addition, they manifest the phenomenon of anticipation, in which the disease tends to present at an earlier age or with greater severity in successive generations. Many additional genes with trinucleotide repeats are believed to be expressed in the human brain. As anticipation has been reported in schizophrenia and bipolar affective disorder, we have examined allele distributions of 13 trinucleotide repeat-containing genes, many novel and all expressed in the brain, in genomic DNA from schizophrenic (n = 20–97) and bipolar affective disorder patients (23–30) and controls (n = 43–146). No evidence was obtained to implicate expanded alleles in these 13 genes as causal factors in these diseases. © 1996 Wiley-Liss, Inc.     

Targeted genome screen of panic disorder and anxiety disorder proneness using homology to murine QTL regions*

Family and twin studies have indicated that genes influence susceptibility to panic and phobic anxiety disorders, but the location of the genes involved remains unknown. Animal models can simplify gene‐mapping efforts by overcoming problems that complicate human pedigree studies including genetic heterogeneity and high phenocopy rates. Homology between rodent and human genomes can be exploited to map human genes underlying complex traits. We used regions identified by quantitative trait locus (QTL)‐mapping of anxiety phenotypes in mice to guide a linkage analysis of a large multiplex pedigree (99 members, 75 genotyped) segregating panic disorder/agoraphobia. Two phenotypes were studied: panic disorder/agoraphobia and a phenotype (“D‐type”) designed to capture early‐onset susceptibility to anxiety disorders. A total of 99 markers across 11 chromosomal regions were typed. Parametric lod score analysis provided suggestive evidence of linkage (lod = 2.38) to a locus on chromosome 10q under a dominant model with reduced penetrance for the anxiety‐proneness (D‐type) phenotype. Nonparametric (NPL) analysis provided evidence of linkage for panic disorder/agoraphobia to a locus on chromosome 12q13 (NPL = 4.96, P = 0.006). Modest evidence of linkage by NPL analysis was also found for the D‐type phenotype to a region of chromosome 1q (peak NPL = 2.05, P = 0.035). While these linkage results are merely suggestive, this study illustrates the potential advantages of using mouse gene‐mapping results and exploring alternative phenotype definitions in linkage studies of anxiety disorder. © 2001 Wiley‐Liss, Inc.     

Evidence of susceptibility loci on 4q32 and 16p12 for bipolar disorder

We performed a genome-wide scan for susceptibility loci in bipolar disorder in a study sample colleted from the isolated Finnish population, consisting of 41 families with at least two affected siblings. We identified one distinct locus on 16p12 providing significant evidence for linkage in two-point analysis (Z(max)=3.4). Furthermore, three loci with a two-point LOD score >2.0 were observed with markers on 4q32, 12q23 and Xq25, the latter locus having been earlier identified in one extended Finnish pedigree. In the second stage we fine mapped these chromosomal regions and also genotyped additional family members. In the fine mapping stage, 4q32 provided significant evidence of linkage for the three-point analyses (Z(max)=3.6) and 16p12 produced a three-point LOD score of 2.7. Since the identified chromosomal regions replicate earlier linkage findings in either bipolar disorder or other mental disorders, they should be considered good targets for further genetic analyses.     

Search for bipolar disorder susceptibility loci: The application of a modified genome scan concentrating on gene‐rich regions

Conducting genome wide screens for evidence of genetic linkage has become a well‐established method for identifying regions of the human genome harboring susceptibility loci for complex disorders. For bipolar disorder, a number of such studies have been performed, and several regions of the genome have potentially been implicated in the disorder. The classic design for a genome screen involves examining polymorphic genetic markers spaced at regular intervals throughout the genome, typically every 10 cM, for evidence of linkage. An alternative design, based on the observation that genes do not appear to be evenly distributed, was proposed, enabling the number of markers examined in a genome wide screen to be reduced. This article describes the application of such a modified screen to a collection of 48 Irish families with bipolar disorder, comprising a total of 82 affected sib‐pairs. From the results obtained a number of regions are highlighted for further study. One of these regions (17q11.1‐q12) coincides with the location of a candidate gene, the serotonin transporter, whereas others concur with the findings of published studies. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:728–732, 2000. © 2000 Wiley‐Liss, Inc.     

Genetic refinement and physical mapping of a chromosome 18q candidate region for bipolar disorder.

Recent genetic studies have implicated chromosome 18 in bipolar disorder (BP) with putative loci in the pericentromeric region and on 18q. We reported linkage to chromosome 18q21.33-q23 in a large family. In this study we typed additional markers in the family and were able to reduce the candidate region significantly. All affected family members are sharing alleles for markers spanning a genetic distance of maximal 8.9 cM. Haplotype analysis provided a marker order in agreement with published genetic and physical maps. Using yeast artificial chromosomes, we constructed a contig map that will help to identify positional candidate genes for bipolar disorder.     

Possible locus for bipolar disorder near the dopamine transporter on chromosome 5

The dopamine transporter (DAT) plays a key role in the regulation of dopaminergic neurotransmission by mediating the active reuptake of synaptic dopamine. It is an important candidate gene for bipolar disorder because of data implicating dopamine abnormalities in mania, and because it is the site of action of amphetamine, which has activating and psychotogenic properties. DAT has recently been cloned by its homology to a family of transporters, and mapped to chromosome 5p15.3. We tested DAT for linkage to bipolar disorder in a collection of 21 families from the general North American population (University of California, San Diego/University of British Columbia [UCSD/UBC] families), three Icelandic pedigrees, and Old Order Amish pedigree 110. We examined three markers at DAT, including a 5′ TaqI RFLP (HDAT-TaqI), a highly polymorphic variable number of tandem repeats marker (VNTR) (HDAT-VNTR1), and a 3′ 40-bp repeat marker (HDAT-PCR1), as well as two nearby microsatellite markers, D5S392 and D5S406. A maximum lod score of 2.38 was obtained at D5S392 in one of the UCSD/UBC families under an autosomal-dominant model. A lod score of 1.09 was also obtained under the same dominant model in the Amish at HDAT-PCR1. In the combined set of families, a maximum lod score of 1.76 was obtained under an autosomal-recessive model at HDAT-TaqI. Positive results were also obtained at several markers, using three non-parametric methods in the UCSD/UBC family set: the affected pedigree member method (P = 0.001), an affected sib pair method (ESPA, P = 0.0008), and the transmission disequilibrium test (P = 0.024). These results suggest the presence of a susceptibility locus for bipolar disorder near the DAT locus on chromosome 5. © 1996 Wiley-Liss, Inc.     

Search for bipolar disorder susceptibility loci: the application of a modified genome scan concentrating on gene-rich regions

Conducting genome wide screens for evidence of genetic linkage has become a well-established method for identifying regions of the human genome harboring susceptibility loci for complex disorders. For bipolar disorder, a number of such studies have been performed, and several regions of the genome have potentially been implicated in the disorder. The classic design for a genome screen involves examining polymorphic genetic markers spaced at regular intervals throughout the genome, typically every 10 cM, for evidence of linkage. An alternative design, based on the observation that genes do not appear to be evenly distributed, was proposed, enabling the number of markers examined in a genome wide screen to be reduced. This article describes the application of such a modified screen to a collection of 48 Irish families with bipolar disorder, comprising a total of 82 affected sib-pairs. From the results obtained a number of regions are highlighted for further study. One of these regions (17q11.1-q12) coincides with the location of a candidate gene, the serotonin transporter, whereas others concur with the findings of published studies. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:728-732, 2000.     

Linkage disequilibrium mapping of bipolar affective disorder at 12q23-q24 provides evidence for association at CUX2 and FLJ32356.

Chromosome 12q23-q24 has been implicated by several linkage studies as harboring a gene for bipolar affective disorder. We performed linkage disequilibrium (LD) mapping with 17 microsatellite markers across a 1.6 Mb-wide segment forming the central part of our narrowest linkage region. A significant signal (P = 0.0016) was identified for one microsatellite marker in our UK Caucasian case-control sample (347 cases, 374 controls). Genes, including regulatory elements, around this marker were screened for mutations and the LD structure of the region determined by genotyping 22 SNPs and insertion/deletion polymorphisms in 94 individuals. A set of 11 haplotype tagging (ht) SNPs was genotyped in our sample using a two-stage procedure. Two SNPs (rs3847953 and rs933399) and an insertion/deletion with putative functional relevance (which are in high LD with each other and with the microsatellite marker) showed significant or nearly significant association with bipolar disorder after Bonferroni-correction (reaching nominal P values from P = 0.002 to P = 0.005). In a sample of 110 UK Caucasian parent-offspring trios there was a trend for an over transmission in the same direction that failed to meet conventional levels of statistical significance. Our data provide evidence for association between bipolar mood disorder and markers on chromosome 12q23-q24 but need replication in independent samples.