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1.  Does APOE Explain the Linkage of Alzheimer’s Disease to Chromosome 19q13? 
We have studied the impact of the apolipoprotein E gene (APOE) on the chromosome 19 linkage peak from an analysis of sib-pairs affected by Alzheimer’s disease. We genotyped 417 affected sib-pairs (ASPs) collected in Sweden and Norway (SWE), the UK and the USA for 10 microsatellite markers on chromosome 19. The highest Zlr (3.28, chromosome-wide P-value 0.036) from the multipoint linkage analysis was located approximately 1 Mb from APOE, at marker D19S178. The linkage to chromosome 19 was well explained by APOE in the whole sample as well as in the UK and USA subsamples, as identity by descent (IBD) increased with the number of ε4 alleles in ASPs. There was a suggestion from the SWE subsample that linkage was higher than would be expected from APOE alone, although the test for this did not reach formal statistical significance. There was also a significant age at onset (aao) effect on linkage to chromosome 19q13 in the whole sample, which manifested itself as increased IBD sharing in relative pairs with lower mean aao. This effect was partially, although not completely, explained by APOE. The aao effect varied considerably between the different subsamples, with most of the effect coming from the UK sample. The other samples showed smaller effects in the same direction, but these were not significant.
doi:10.1002/ajmg.b.30681
PMCID: PMC2726752  PMID: 18161859
Alzheimer’s disease; APOE; linkage; age at onset; apolipoprotein E
2.  LDGIdb: a database of gene interactions inferred from long-range strong linkage disequilibrium between pairs of SNPs 
BMC Research Notes  2012;5:212.
Background
Complex human diseases may be associated with many gene interactions. Gene interactions take several different forms and it is difficult to identify all of the interactions that are potentially associated with human diseases. One approach that may fill this knowledge gap is to infer previously unknown gene interactions via identification of non-physical linkages between different mutations (or single nucleotide polymorphisms, SNPs) to avoid hitchhiking effect or lack of recombination. Strong non-physical SNP linkages are considered to be an indication of biological (gene) interactions. These interactions can be physical protein interactions, regulatory interactions, functional compensation/antagonization or many other forms of interactions. Previous studies have shown that mutations in different genes can be linked to the same disorders. Therefore, non-physical SNP linkages, coupled with knowledge of SNP-disease associations may shed more light on the role of gene interactions in human disorders. A user-friendly web resource that integrates information about non-physical SNP linkages, gene annotations, SNP information, and SNP-disease associations may thus be a good reference for biomedical research.
Findings
Here we extracted the SNPs located within the promoter or exonic regions of protein-coding genes from the HapMap database to construct a database named the Linkage-Disequilibrium-based Gene Interaction database (LDGIdb). The database stores 646,203 potential human gene interactions, which are potential interactions inferred from SNP pairs that are subject to long-range strong linkage disequilibrium (LD), or non-physical linkages. To minimize the possibility of hitchhiking, SNP pairs inferred to be non-physically linked were required to be located in different chromosomes or in different LD blocks of the same chromosomes. According to the genomic locations of the involved SNPs (i.e., promoter, untranslated region (UTR) and coding region (CDS)), the SNP linkages inferred were categorized into promoter-promoter, promoter-UTR, promoter-CDS, CDS-CDS, CDS-UTR and UTR-UTR linkages. For the CDS-related linkages, the coding SNPs were further classified into nonsynonymous and synonymous variations, which represent potential gene interactions at the protein and RNA level, respectively. The LDGIdb also incorporates human disease-association databases such as Genome-Wide Association Studies (GWAS) and Online Mendelian Inheritance in Man (OMIM), so that the user can search for potential disease-associated SNP linkages. The inferred SNP linkages are also classified in the context of population stratification to provide a resource for investigating potential population-specific gene interactions.
Conclusion
The LDGIdb is a user-friendly resource that integrates non-physical SNP linkages and SNP-disease associations for studies of gene interactions in human diseases. With the help of the LDGIdb, it is plausible to infer population-specific SNP linkages for more focused studies, an avenue that is potentially important for pharmacogenetics. Moreover, by referring to disease-association information such as the GWAS data, the LDGIdb may help identify previously uncharacterized disease-associated gene interactions and potentially lead to new discoveries in studies of human diseases.
Keywords
Gene interaction, SNP, Linkage disequilibrium, Systems biology, Bioinformatics
doi:10.1186/1756-0500-5-212
PMCID: PMC3441865  PMID: 22551073
3.  Dense genome-wide SNP linkage scan in 301 hereditary prostate cancer families identifies multiple regions with suggestive evidence for linkage 
Human Molecular Genetics  2009;18(10):1839-1848.
The search for susceptibility loci in hereditary prostate cancer (HPC) has proven challenging due to genetic and disease heterogeneity. Multiple risk loci have been identified to date, however few loci have been replicated across independent linkage studies. In addition, most previous analyses have been hampered by the relatively poor information content provided by microsatellite scans. To overcome these issues, we have performed linkage analyses on members of 301 HPC families genotyped using the Illumina SNP linkage panel IVb. The information content for this panel, averaged over all pedigrees and all chromosomes, was 86% (range 83–87% over chromosomes). Analyses were also stratified on families according to disease aggressiveness, age at diagnosis and number of affected individuals to achieve more genetically homogeneous subsets. Suggestive evidence for linkage was identified at 7q21 (HLOD = 1.87), 8q22 (KCLOD = 1.88) and 15q13–q14 (HLOD = 1.99) in 289 Caucasian families, and nominal evidence for linkage was identified at 2q24 (LOD = 1.73) in 12 African American families. Analysis of more aggressive prostate cancer phenotypes provided evidence for linkage to 11q25 (KCLOD = 2.02), 15q26 (HLOD = 1.99) and 17p12 (HLOD = 2.13). Subset analyses according to age at diagnosis and number of affected individuals also identified several regions with suggestive evidence for linkage, including a KCLOD of 2.82 at 15q13–q14 in 128 Caucasian families with younger ages at diagnosis. The results presented here provide further evidence for a prostate cancer susceptibility locus on chromosome 15q and demonstrate the power of utilizing high information content SNP scans in combination with homogenous collections of large prostate cancer pedigrees.
doi:10.1093/hmg/ddp100
PMCID: PMC2671990  PMID: 19251732
4.  Evidence for Three Loci Modifying Age-at-Onset of Alzheimer’s Disease in Early-Onset PSEN2 Families 
Families with early-onset Alzheimer’s disease (AD) sharing a single PSEN2 mutation exhibit a wide range of age-at-onset, suggesting that modifier loci segregate within these families. While APOE is known to be an age-at-onset modifier, it does not explain all of this variation. We performed a genome scan within nine such families for loci influencing age-at-onset, while simultaneously controlling for variation in the primary PSEN2 mutation (N141I) and APOE. We found significant evidence of linkage between age-at-onset and chromosome 1q23.3 (P < 0.001) when analysis included all families, and to chromosomes 1q23.3 (P < 0.001), 17p13.2 (P = 0.0002), 7q33 (P = 0.017), and 11p14.2 (P = 0.017) in a single large pedigree. Simultaneous analysis of these four chromosomes maintained strong evidence of linkage to chromosomes 1q23.3 and 17p13.2 when all families were analyzed, and to chromosomes 1q23.3, 7q33, and 17p13.2 within the same single pedigree. Inclusion of major gene covariates proved essential to detect these linkage signals, as all linkage signals dissipated when PSEN2 and APOE were excluded from the model. The four chromosomal regions with evidence of linkage all coincide with previous linkage signals, associated SNPs, and/or candidate genes identified in independent AD study populations. This study establishes several candidate regions for further analysis and is consistent with an oligogenic model of AD risk and age-at-onset. More generally, this study also demonstrates the value of searching for modifier loci in existing datasets previously used to identify primary causal variants for complex disease traits.
doi:10.1002/ajmg.b.31072
PMCID: PMC3022037  PMID: 20333730
genome-scan; modifier scan; quantitative trait; complex disease; dementia
5.  Significant linkage at chromosome 19q for otitis media with effusion and/or recurrent otitis media (COME/ROM) 
BMC Medical Genetics  2011;12:124.
Background
In previous analyses, we identified a region of chromosome 19 as harboring a susceptibility locus for chronic otitis media with effusion and/or recurrent otitis media (COME/ROM). Our aim was to further localize the linkage signal and ultimately identify the causative variant or variants. We followed up our previous linkage scan with dense SNP genotyping across in a 5 Mb region. A total of 607 individuals from 139 families, including 159 affected sib pairs and 62 second-degree affected relative pairs, were genotyped at 1,091 SNPs. We carried out a nonparametric linkage analysis, modeling marker-to-marker linkage disequilibrium.
Results
The maximum log of the odds (LOD) score increased to 3.75 (P = 1.6 × 10-5) at position 63.4 Mb, with a LOD-1 support interval between 61.6 Mb and 63.8 Mb, providing significant evidence of linkage between this region and COME/ROM. The support interval contains over 90 known genes, including several genes involved in the inflammasome protein complex, a key regulator of the innate immune response to harmful exogenous or endogenous stimuli. Parametric linkage analysis suggests that for a sib of an affected individual, the recurrence risk of COME/ROM due to this linkage region is twice the recurrence risk in the population. We examined potential associations between the SNPs genotyped in this region and COME/ROM, however none provided evidence for association.
Conclusion
This study has refined the 19q region of linkage with COME/ROM, and association results suggest that the linkage signal may be due to rare variants.
doi:10.1186/1471-2350-12-124
PMCID: PMC3191346  PMID: 21943191
Linkage; fine mapping; otolaryngology
6.  Three-color single molecule imaging shows WASP detachment from Arp2/3 complex triggers actin filament branch formation 
eLife  2013;2:e01008.
During cell locomotion and endocytosis, membrane-tethered WASP proteins stimulate actin filament nucleation by the Arp2/3 complex. This process generates highly branched arrays of filaments that grow toward the membrane to which they are tethered, a conflict that seemingly would restrict filament growth. Using three-color single-molecule imaging in vitro we revealed how the dynamic associations of Arp2/3 complex with mother filament and WASP are temporally coordinated with initiation of daughter filament growth. We found that WASP proteins dissociated from filament-bound Arp2/3 complex prior to new filament growth. Further, mutations that accelerated release of WASP from filament-bound Arp2/3 complex proportionally accelerated branch formation. These data suggest that while WASP promotes formation of pre-nucleation complexes, filament growth cannot occur until it is triggered by WASP release. This provides a mechanism by which membrane-bound WASP proteins can stimulate network growth without restraining it.
DOI: http://dx.doi.org/10.7554/eLife.01008.001
eLife digest
Most cells are neither perfect spheres nor amorphous blobs, but instead have characteristic shapes that enable them to carry out specific roles within tissues or organs. These shapes are established by a type of scaffolding, called the cytoskeleton, that gives structure to the cell, and also forms networks over which other proteins, and even organelles, can travel.
The filaments that make up the cytoskeleton are composed of various proteins, one of which is called actin. Cellular actin filaments can grow by adding new actin molecules, and actin filaments can also have ‘branches’ that fork out from the mother filament. Branches grow out of an assembly of seven proteins known as the Arp2/3 complex, which attaches to the side of the mother filament. Branch growth is triggered by binding to the Arp2/3 complex of an additional protein, WASP, but the sequence of events required to initiate a new branch is not well understood. In particular, WASP is bound to cell membranes; at some point it must detach from the Arp2/3 complex so that the nearness of the membrane does not interfere with the growth of branches. Now, Smith et al. uncover how branch formation is triggered, and define a new role played by WASP in this process.
It is known that a specific region of the WASP protein called the VCA domain binds to both the Arp2/3 complex and actin. Smith et al. studied how this domain could initiate branch formation, and showed that a pair of VCA domains linked to each other, along with an Arp2/3 complex, could interact jointly with an existing actin filament before a new branch formed. However, new branches did not form unless the VCA-domain pair detached from the actin filament, leaving the Arp2/3 complex behind. Additionally, Smith et al. found that mutant VCA-domain pairs detached from the actin filament at different rates, which then determined the chance that a new branch formed.
These findings—and those of Helgeson and Nolen published concurrently in eLife—suggest that, in cells, two WASP proteins first recruit the Arp2/3 complex to the membrane, and that together they interact with an existing actin filament. The WASP proteins then release the filament, and only then does the Arp2/3 complex initiate the formation of an actin branch. Since the Arp2/3 complex is no longer attached to WASP, subsequent growth of the branch is not physically limited by linkage to the membrane.
DOI: http://dx.doi.org/10.7554/eLife.01008.002
doi:10.7554/eLife.01008
PMCID: PMC3762362  PMID: 24015360
TIRF; WH2; nucleation; Wiskott-Aldrich syndrome protein; verprolin homology; activation; Human; S. cerevisiae
7.  Identification of a novel psoriasis susceptibility locus at 1p and evidence of epistasis between PSORS1 and candidate loci 
Journal of Medical Genetics  2001;38(1):7-13.
The pathogenesis of all forms of psoriasis remains obscure. Segregation analysis and twin studies together with ethnic differences in disease frequency all point to an underlying genetic susceptibility to psoriasis, which is both complex and likely to reflect the action of a number of genes. We performed a genome wide analysis using a total of 271 polymorphic autosomal markers on 284 sib relative pairs identified within 158 independent families. We detected evidence for linkage at 6p21 (PSORS1) with a non-parametric linkage score (NPL)=4.7, p=2 × 10-6 and at chromosome 1p (NPL=3.6, p=1.9 × 10-4) in all families studied. Significant excess (p=0.004) paternal allele sharing was detected for markers spanning the PSORS1 locus. A further three regions reached NPL scores of 2 or greater, including a region at chromosome 7 (NPL 2.1), for which linkage for a number of autoimmune disorders has been reported. Partitioning of the data set according to allele sharing at 6p21 (PSORS1) favoured linkage to chromosomes 2p (NPL 2.09) and 14q (NPL 2.0), both regions implicated in previous independent genome scans, and suggests evidence for epistasis between PSORS1 and genes at other genomic locations. This study has provided linkage evidence in favour of a novel susceptibility locus for psoriasis and provides evidence of the complex mechanisms underlying the genetic predisposition to this common skin disease.


Keywords: psoriasis; PSORS1; epistasis
doi:10.1136/jmg.38.1.7
PMCID: PMC1734710  PMID: 11134234
8.  Genome-Wide Scan for Linkage to Type 1 Diabetes in 2,496 Multiplex Families From the Type 1 Diabetes Genetics Consortium 
Diabetes  2009;58(4):1018-1022.
OBJECTIVE
Type 1 diabetes arises from the actions of multiple genetic and environmental risk factors. Considerable success at identifying common genetic variants that contribute to type 1 diabetes risk has come from genetic association (primarily case-control) studies. However, such studies have limited power to detect genes containing multiple rare variants that contribute significantly to disease risk.
RESEARCH DESIGN AND METHODS
The Type 1 Diabetes Genetics Consortium (T1DGC) has assembled a collection of 2,496 multiplex type 1 diabetic families from nine geographical regions containing 2,658 affected sib-pairs (ASPs). We describe the results of a genome-wide scan for linkage to type 1 diabetes in the T1DGC family collection.
RESULTS
Significant evidence of linkage to type 1 diabetes was confirmed at the HLA region on chromosome 6p21.3 (logarithm of odds [LOD] = 213.2). There was further evidence of linkage to type 1 diabetes on 6q that could not be accounted for by the major linkage signal at the HLA class II loci on chromosome 6p21. Suggestive evidence of linkage (LOD ≥2.2) was observed near CTLA4 on chromosome 2q32.3 (LOD = 3.28) and near INS (LOD = 3.16) on chromosome 11p15.5. Some evidence for linkage was also detected at two regions on chromosome 19 (LOD = 2.84 and 2.54).
CONCLUSIONS
Five non–HLA chromosome regions showed some evidence of linkage to type 1 diabetes. A number of previously proposed type 1 diabetes susceptibility loci, based on smaller ASP numbers, showed limited or no evidence of linkage to disease. Low-frequency susceptibility variants or clusters of loci with common alleles could contribute to the linkage signals observed.
doi:10.2337/db08-1551
PMCID: PMC2661598  PMID: 19136655
9.  Tourette disorder spectrum maps to chromosome 14q31.1 in an Italian kindred 
Neurogenetics  2010;11(4):417-423.
Tourette syndrome (TS) is a frequent neuropsychiatric disorder of unknown etiology. A number of chromosomal regions have been nominated as TS loci in linkage studies, but confirmation has met with limited success and causative mutations have not yet been definitely identified. Furthermore, TS, chronic tics, and obsessive–compulsive disorder (OCD) occur at increased frequencies among TS relatives, supporting the view that these phenotypes represent parts of the same genetically determined spectrum. We ascertained a four-generation Italian kindred segregating TS, chronic multiple motor tics (CMT), and OCD, and we performed a ten-centimorgan (cM) genome-wide linkage scan in order to map the underlying genetic defect. Suggestive linkage to chromosome 14q31.1 (multipoint LOD = 2.4) was detected by affected-only analysis under an autosomal dominant model and a narrower phenotype definition (only the subjects with TS and CMT were considered as affected). The linkage peak increased and it approached genome-wide significance (LOD = 3.29) when a broader phenotype definition was adopted (subjects with TS, CMT, and OCD considered as affected). Haplotype analysis defined a ∼2.3 cM critical region, shared by all the relatives with TS, CMT, or OCD. In conclusion, we provide strong evidence for linkage of TS spectrum to chromosome 14q31.1. Suggestive linkage to an overlapping region of chromosome 14q was reported in a recent scan of TS sibling pairs. This region might therefore contain an important gene for TS, and it should be prioritized for further study.
Electronic supplementary material
The online version of this article (doi:10.1007/s10048-010-0244-7) contains supplementary material, which is available to authorized users.
doi:10.1007/s10048-010-0244-7
PMCID: PMC2956568  PMID: 20437249
Tourette syndrome; Tics; Movement disorders; Linkage mapping; Locus
10.  Genome-Wide Mapping of Susceptibility to Coronary Artery Disease Identifies a Novel Replicated Locus on Chromosome 17 
PLoS Genetics  2006;2(5):e72.
Coronary artery disease (CAD) is a leading cause of death world-wide, and most cases have a complex, multifactorial aetiology that includes a substantial heritable component. Identification of new genes involved in CAD may inform pathogenesis and provide new therapeutic targets. The PROCARDIS study recruited 2,658 affected sibling pairs (ASPs) with onset of CAD before age 66 y from four European countries to map susceptibility loci for CAD. ASPs were defined as having CAD phenotype if both had CAD, or myocardial infarction (MI) phenotype if both had a MI. In a first study, involving a genome-wide linkage screen, tentative loci were mapped to Chromosomes 3 and 11 with the CAD phenotype (1,464 ASPs), and to Chromosome 17 with the MI phenotype (739 ASPs). In a second study, these loci were examined with a dense panel of grid-tightening markers in an independent set of families (1,194 CAD and 344 MI ASPs). This replication study showed a significant result on Chromosome 17 (MI phenotype; p = 0.009 after adjustment for three independent replication tests). An exclusion analysis suggests that further genes of effect size λsib > 1.24 are unlikely to exist in these populations of European ancestry. To our knowledge, this is the first genome-wide linkage analysis to map, and replicate, a CAD locus. The region on Chromosome 17 provides a compelling target within which to identify novel genes underlying CAD. Understanding the genetic aetiology of CAD may lead to novel preventative and/or therapeutic strategies.
Synopsis
Coronary artery disease (CAD), which presents clinically as a heart attack (myocardial infarction) or angina, is a leading cause of death world-wide. The aetiology of CAD is complex with a substantial heritable component. Although there is a huge knowledge-base detailing many aspects of the underlying pathophysiology of CAD, it is likely that undiscovered pathways exist. Positional cloning projects can identify novel susceptibility genes; in the first step genome-wide linkage screens are used to assign loci to specific chromosomes.
The authors have collected 2,036 CAD families from four European countries, in order to maximise the power of detecting genes that confer modest risks. A genome-wide linkage scan identified three promising regions for intensive study; one of the linked regions (Chromosome 17) was confined to families with multiple cases of myocardial infarction and was replicated in a second independent series of families. In addition the linkage scan confirmed a previously identified locus on Chromosome 2. These results demonstrate that novel CAD susceptibility genes are tractable to positional cloning which promises to lead to the identification of new molecular insights into this condition, and hopefully, new treatments.
doi:10.1371/journal.pgen.0020072
PMCID: PMC1463045  PMID: 16710446
11.  Immunogenetics of leishmanial and mycobacterial infections: the Belem Family Study. 
In the 1970s and 1980s, analysis of recombinant inbred, congenic and recombinant haplotype mouse strains permitted us to effectively 'scan' the murine genome for genes controlling resistance and susceptibility to leishmanial infections. Five major regions of the genome were implicated in the control of infections caused by different Leishmania species which, because they show conserved synteny with regions of the human genome, immediately provides candidate gene regions for human disease susceptibility genes. A common intramacrophage niche for leishmanial and mycobacterial pathogens, and a similar spectrum of immune response and disease phenotypes, also led to the prediction that the same genes/candidate gene regions might be responsible for genetic susceptibility to mycobacterial infections such as leprosy and tuberculosis. Indeed, one of the murine genes (Nramp1) was identified for its role in controlling a range of intramacrophage pathogens including leishmania, salmonella and mycobacterium infections. In recent studies, multicase family data on visceral leishmaniasis and the mycobacterial diseases, tuberculosis and leprosy, have been collected from north-eastern Brazil and analysed to determine the role of these candidate genes/regions in determining disease susceptibility. Complex segregation analysis provides evidence for one or two major genes controlling susceptibility to tuberculosis in this population. Family-based linkage analyses (combined segregation and linkage analysis; sib-pair analysis), which have the power to detect linkage between marker loci in candidate gene regions and the putative disease susceptibility genes over 10-20 centimorgans, and transmission disequilibrium testing, which detects allelic associations over 1 centimorgan (ca. 1 megabase), have been used to examine the role of four regions in determining disease susceptibility and/or immune response phenotype. Our results demonstrate: (i) the major histocompatibility complex (MHC: H-2 in mouse, HLA in man: mouse chromosome 17/human 6p; candidates class II and class III including TNF alpha/beta genes) shows both linkage to, and allelic association with, leprosy per se, but is only weakly associated with visceral leishmaniasis and shows neither linkage to nor allelic association with tuberculosis; (ii) no evidence for linkage between NRAMP1, the positionally cloned candidate for the murine macrophage resistance gene Ity/Lsh/Bcg (mouse chromosome 1/human 2q35), and susceptibility to tuberculosis or visceral leishmaniasis could be demonstrated in this Brazilian population; (iii) the region of human chromosome 17q (candidates NOS2A, SCYA2-5) homologous with distal mouse chromosome 11, originally identified as carrying the Scl1 gene controlling healing versus nonhealing responses to Leishmania major, is linked to tuberculosis susceptibility; and (iv) the 'T helper 2' cytokine gene cluster (proximal murine chromosome 11/human 5q; candidates IL4, IL5, IL9, IRF1, CD14) controlling later phases of murine L. major infection, is not linked to human disease susceptibility for any of the three infections, but shows linkage to and highly significant allelic association with ability to mount an immune response to mycobacterial antigens. These studies demonstrate that the 'mouse-to-man' strategy, refined by our knowledge of the human immune response to infection, can lead to the identification of important candidate gene regions in man.
PMCID: PMC1692031  PMID: 9355125
12.  Genome wide scan in a Flemish inflammatory bowel disease population: support for the IBD4 locus, population heterogeneity, and epistasis 
Gut  2004;53(7):980-986.
Background and aims: Genome wide scans in inflammatory bowel disease (IBD) have indicated various susceptibility regions with replication of 16cen (IBD1), 12q (IBD2), 6p (IBD3), 14q11 (IBD4), and 3p21. As no linkage was previously found on IBD regions 3, 7, 12, and 16 in Flemish IBD families, a genome wide scan was performed to detect other susceptibility regions in this population.
Methods: A cohort of 149 IBD affected relative pairs, all recruited from the Northern Flemish part of Belgium, were genotyped using microsatellite markers at 12 cM intervals, and analysed by Genehunter non-parametric linkage software. All families were further genotyped for the three main Crohn’s disease associated variants in the NOD2/CARD15 gene.
Results: Nominal evidence for linkage was observed on chromosomes 1 (D1S197: multipoint non-parametric linkage (NPL) score 2.57, p = 0.004; and at D1S305-D1S252: NPL 2.97, p = 0.001), 4q (D4S406: NPL 1.95, p = 0.03), 6q16 (D6S314: NPL 2.44, p = 0.007), 10p12 (D10S197: NPL 2.05, p = 0.02), 11q22 (D11S35-D11S927: NPL 1.95, p = 0.02) 14q11-12 (D14S80: NPL 2.41, p = 0.008), 20p12 (D20S192: NPL 2.7, p = 0.003), and Xq (DXS990: NPL 1.70, p = 0.04). A total of 51.4% of patients carried at least one NOD2/CARD15 variant. Furthermore, epistasis was observed between susceptibility regions 6q/10p and 20p/10p.
Conclusion: Genome scanning in a Flemish IBD population found nominal evidence for linkage on 1p, 4q, 10p12, and 14q11, overlapping with other genome scan results, with linkage on 14q11-12 supporting the IBD4 locus. The results further show that epistasis is contributing to the complex model of IBD and indicate that population heterogeneity is not to be underestimated. Finally, NOD2/CARD15 is clearly implicated in the Flemish IBD population.
doi:10.1136/gut.2003.034033
PMCID: PMC1774099  PMID: 15194648
inflammatory bowel disease; genome scan; genetics
13.  Genome scan in familial late-onset Alzheimer’s disease: a locus on chromosome 6 contributes to age at onset 
Alzheimer’s disease (AD) is a common, genetically complex, fatal neurodegenerative disorder of late life. Although several genes are known to play a role in early-onset AD, identification of the genetic basis of late onset AD (LOAD) has been challenging, with only the APOE gene known to have a high contribution to both AD risk and age-at-onset. Here we present the first genome-scan analysis of the complete, well-characterized University of Washington LOAD sample of 119 pedigrees, using age-at-onset as the trait of interest. The analysis approach used allows for a multilocus trait model while at the same time accommodating age censoring, effects of APOE as a known genetic covariate, and full pedigree and marker information. The results provide strong evidence for linkage of loci contributing to age-at-onset to genomic regions on chromosome 6q16.3, and to 19q13.42 in the region of the APOE locus. There was evidence for interaction between APOE and the locus on chromosome 6q and suggestive evidence for linkage to chromosomes 11p13, 15q12-14, and 19p13.12. These results provide the first independent confirmation of an AD age-at-onset locus on chromosome 6 and suggest that further efforts towards identifying the underlying causal locus or loci are warranted.
doi:10.1002/ajmg.b.32133
PMCID: PMC3654841  PMID: 23355194
linkage analysis; MCMC; oligogenic; dementia; age-censored
14.  Genome scan of age-at-onset in the NIMH Alzheimer disease sample uncovers multiple loci, along with evidence of both genetic and sample heterogeneity 
Alzheimer’s disease (AD) is a common neurodegenerative disorder of late life with a complex genetic basis. Although several genes are known to play a role in rare early-onset AD, only the APOE gene is known to have a high contribution to risk of the common late-onset form of the disease (LOAD, onset > 60 years). APOE genotypes vary in their AD risk as well as age-at-onset distributions, and it is likely that other loci will similarly affect AD age-at-onset. Here we present the first analysis of age-at-onset in the NIMH LOAD sample that allows for both a multilocus trait model and genetic heterogeneity among the contributing sites, while at the same time accommodating age censoring, effects of known genetic covariates, and full pedigree and marker information. The results provide evidence for genomic regions not previously implicated in this data set, including regions on chromosomes 7q, 15, and 19p. They also affirm evidence for loci on chromosomes 1q, 6p, 9q, 11, and, of course, the APOE locus on 19q, all of which have been reported previously in the same sample. The analyses failed to find evidence for linkage to chromosome 10 with inclusion of unaffected subjects and extended pedigrees. Several regions implicated in these analyses in the NIMH sample have been previously reported in genome scans of other AD samples. These results, therefore, provide independent confirmation of AD loci in family-based samples on chromosomes 1q, 7q, 19p, and suggest that further efforts towards identifying the underlying causal loci are warranted.
doi:10.1002/ajmg.b.31220
PMCID: PMC3168696  PMID: 21812099
MCMC; oligogenic; Bayesian; dementia; linkage analysis
15.  A genome-wide scan to identify loci for smoking rate in the Framingham Heart Study population 
BMC Genetics  2003;4(Suppl 1):S103.
Background
Although many years of genetic epidemiological studies have demonstrated that genetics plays a significant role in determining smoking behavior, little information is available on genomic loci or genes affecting nicotine dependence. Several susceptibility chromosomal regions for nicotine dependence have been reported, but few have received independent confirmation. To identify susceptibility loci for nicotine dependence, 313 extended pedigrees selected from the Framingham Heart Study population were analyzed by both the GENEHUNTER and S.A.G.E. programs.
Results
After performing linkage analyses on the 313 extended Framingham Heart Study families, the EM Haseman-Elston method implemented in GENEHUNTER provided evidence for significant linkage of smoking rate to chromosome 11 and suggestive linkage to chromosomes 9, 14, and 17. Multipoint sib-pair regression analysis using the SIBPAL program of S.A.G.E. on 1389 sib pairs that were split from the 313 extended families identified suggestive linkage of smoking rate to chromosomes 4, 7, and 17. Of these identified positive regions for nicotine dependence, loci on chromosomes 7, 11, and 17 were identified by both GENEHUNTER and S.A.G.E. programs.
Conclusion
Our genome-wide scan results on the Framingham Heart Study data provide evidence for significant linkage of smoking rate to chromosome 11 and suggestive linkage to chromosomes 4, 7, 9, 14, and 17. These findings suggest that some of these regions may harbor susceptibility loci for nicotine dependence, and warrant further investigation in this and other populations.
doi:10.1186/1471-2156-4-S1-S103
PMCID: PMC1866441  PMID: 14975171
16.  Further evidence of a maternal parent-of-origin effect on chromosome 10 in late-onset Alzheimer’s disease 
The chromosome 10q region has recently received a great deal of attention in late-onset Alzheimer’s disease (LOAD), given the growing evidence of linkage to LOAD, or to A-beta levels, reported by several groups. In a recent paper we reported evidence of linkage in this region in our subset of the NIMH AD Genetics Initiative pedigrees, approaching genome-wide significance (non-parametric LOD score = 3.27), when only families with maternal disease origin were analyzed[1]. We have now extended this work, using an independent subset of NIMH AD pedigrees from the University of Alabama at Birmingham (UAB), and show further evidence of linkage using parent-of-origin information. As in our Hopkins sample, maternal but not paternal pedigrees show significantly increased linkage in the chromosome 10q region compared to the unstratified sample. Combining data from our previous fine-mapping work on this region and five new markers genotyped in all pedigrees results in a non-parametric LOD score of 3.73 in the same region, a value that reaches genome wide significance for linkage, with an empirical p value = 0.003. These results support our earlier findings and narrow the region of interest. In combination with findings from other groups, these results provide further evidence that this chromosome 10 region harbors a gene implicated in LOAD, and our use of parent-of-origin information has been useful in further narrowing the region of interest.
doi:10.1002/ajmg.b.30350
PMCID: PMC2586169  PMID: 16741936
linkage; Alzheimer’s disease; human chromosome 10; genetic imprinting
17.  Genome-wide scan linkage analysis for Parkinson's disease: the European genetic study of Parkinson's disease 
Journal of Medical Genetics  2004;41(12):900-907.
Objective: To undertake a full genome-wide screen for Parkinson's disease susceptibility loci.
Methods: A genome-wide linkage study was undertaken in 227 affected sibling pairs from 199 pedigrees with Parkinson's disease. The pedigree sample consisted of 188 pedigrees from five European countries, and 11 from the USA. Individuals were genotyped for 391 microsatellite markers at ∼10 cM intervals throughout the genome. Multipoint model-free affected sibling pair linkage analyses were carried out using the MLS (maximum LOD score) test.
Results: There were six chromosomal regions with maximum MLS peaks of 1 or greater (pointwise p<0.018). Four of these chromosomal regions appear to be newly identified regions, and the highest MLS values were obtained on chromosomes 11q (MLS = 1.60, at 91 cM, D11S4175) and 7p (MLS = 1.51, at 5 cM, D7S531). The remaining two MLS peaks, on 2p11–q12 and 5q23, are consistent with excess sharing in regions reported by other studies. The highest MLS peak was observed on chromosome 2p11–q12 (MLS = 2.04, between markers D2S2216 and D2S160), within a relatively short distance (∼17 cM) from the PARK3 region. Although a stronger support of linkage to this region was observed in the late age of onset subgroup of families, these differences were not significant. The peak on 5q23 (MLS = 1.05, at 130 cM, D5S471) coincides with the region identified by three other genome scans. All peak locations fell within a 10 cM distance.
Conclusions: These stratified linkage analyses suggest linkage heterogeneity within the sample across the 2p11–q12 and 5q23 regions, with these two regions contributing independently to Parkinson's disease susceptibility.
doi:10.1136/jmg.2004.022632
PMCID: PMC1735631  PMID: 15591275
18.  Genome-Wide Linkage and Admixture Mapping of Type 2 Diabetes in African American Families From the American Diabetes Association GENNID (Genetics of NIDDM) Study Cohort 
Diabetes  2009;58(1):268-274.
OBJECTIVE—We used a single nucleotide polymorphism (SNP) map in a large cohort of 580 African American families to identify regions linked to type 2 diabetes, age of type 2 diabetes diagnosis, and BMI.
RESEARCH DESIGN AND METHODS—After removing outliers and problematic samples, we conducted linkage analysis using 5,914 SNPs in 1,344 individuals from 530 families. Linkage analysis was conducted using variance components for type 2 diabetes, age of type 2 diabetes diagnosis, and BMI and nonparametric linkage analyses. Ordered subset analyses were conducted ranking on age of type 2 diabetes diagnosis, BMI, waist circumference, waist-to-hip ratio, and amount of European admixture. Admixture mapping was conducted using 4,486 markers not in linkage disequilibrium.
RESULTS—The strongest signal for type 2 diabetes (logarithm of odds [LOD] 4.53) was a broad peak on chromosome 2, with weaker linkage to age of type 2 diabetes diagnosis (LOD 1.82). Type 2 diabetes and age of type 2 diabetes diagnosis were linked to chromosome 13p (3–22 cM; LOD 2.42 and 2.46, respectively). Age of type 2 diabetes diagnosis was linked to 18p (66 cM; LOD 2.96). We replicated previous reports on chromosome 7p (79 cM; LOD 2.93). Ordered subset analysis did not overlap with linkage of unselected families. The best admixture score was on chromosome 12 (90 cM; P = 0.0003).
CONCLUSIONS—The linkage regions on chromosomes 7 (27–78 cM) and 18p overlap prior reports, whereas regions on 2p and 13p linkage are novel. Among potential candidate genes implicated are TCF7L1, VAMP5, VAMP8, CDK8, INSIG2, IPF1, PAX8, IL18R1, members of the IL1 and IL1 receptor families, and MAP4K4. These studies provide a complementary approach to genome-wide association scans to identify causative genes for African American diabetes.
doi:10.2337/db08-0931
PMCID: PMC2606884  PMID: 18840782
19.  Evidence for Genes on Chromosome 2 Contributing to Alcohol Dependence With Conduct Disorder and Suicide Attempts 
Twin studies provide strong evidence that there is a shared genetic liability that predisposes to a number of different psychiatric outcomes related to behavioral disinhibition. Further, alcohol dependence comorbid with other disinhibitory disorders is particularly heritable. Chromosome 2p14–2q14.3 has been linked to multiple psychiatric conditions related to behavioral undercontrol. In the Collaborative Study on the Genetics of Alcoholism (COGA), we previously reported linkage to this region with alcohol dependence (AD), suicide attempts (SUI), and conduct disorder (CD). In this study, we follow-up on these previous reports of linkage by combining the phenotypes in analyses that jointly consider the presence of multiple conditions. Linkage analyses of the combined phenotype of AD with CD or SUI results in a maximum LOD score of 5.4 in this region. In addition to this primary linkage peak, independent samples have reported linkage to other alcohol-related phenotypes across chromosome 2. Accordingly, we followed-up these linkage signals by testing for association with SNPs across chromosome 2 in a case–control sample, in which a subset of the cases consisted of alcohol-dependent probands from the linkage sample. We find evidence of association with the combined AD with CD or SUI phenotype, with 23 genes surviving permutation testing. The number of associated genes across the chromosome may explain the persistent linkage findings reported on chromosome 2 across a number of independent studies of alcohol and disinhibitory phenotypes. Further, none of the genes were located directly under the primary COGA linkage peak, which has implications for association tests following-up linkage peaks.
doi:10.1002/ajmg.b.31089
PMCID: PMC3597340  PMID: 20468071
alcoholism; genetics; linkage; association; behavioral disinhibition
20.  A genome wide linkage analysis in Swedish families with hereditary non‐familial adenomatous polyposis/non‐hereditary non‐polyposis colorectal cancer 
Gut  2006;55(3):362-366.
Background and aim
Known colorectal cancer syndromes, such as familial adenomatous polyposis and hereditary non‐polyposis colorectal cancer, have been identified in only a small proportion of cases with a family history of disease. In an attempt to identify loci harbouring novel predisposing genes, we have performed a genome wide linkage analysis in 18 colorectal cancer families recruited from the Department of Clinical Genetics at Karolinska Hospital, Sweden.
Methods
Multipoint parametric and non‐parametric linkage analyses were performed using two affected status criteria, stringent and less stringent. Parametric analysis was performed under the assumption of locus homogeneity and locus heterogeneity.
Results
The initial scan performed using the less stringent affected status criteria revealed regions of interest on chromosome 11 (marker D11S1314: heterogeneity logarithm of odds (HLOD) score 1.96, non‐parametric LOD (NPL) score 1.28; and marker D11S908: HLOD score 2.10, NPL score 2.16) and chromosome 14 (marker D14S258: HLOD score 2.61, NPL score 2.88). Using the stringent affected status criteria, a locus on chromosome 22 was suggested in the parametric analysis (marker D22S315: HLOD score 1.26). After finemapping of the regions on chromosomes 11 and 14, HLOD and NPL scores were reduced but still within the range of suggestive linkage. Haplotype analysis revealed overlapping regions between D11S987 and D11S4207 (proximal region), D11S4120 and D11S4090 (distal region), on chromosome 11, and between D14S1038 and D14S1069 on chromosome 14.
Conclusion
Our study provides evidence of genetic heterogeneity among Swedish colorectal cancer families. Three novel regions were suggested to be of interest in a proportion of families analysed. Further studies are needed to confirm this result.
doi:10.1136/gut.2005.075333
PMCID: PMC1856098  PMID: 16150854
linkage analysis; hereditary non‐polyposis colorectal cancer; familial adenomatous polyposis; colorectal cancer; chromosome 11; chromosome 14; chromosome 22
21.  Evidence of linkage to chromosomes 10p15.3–p15.1, 14q24.3–q31.1 and 9q33.3–q34.3 in non-syndromic colorectal cancer families 
Up to 25% of colorectal cancer (CRC) may be caused by inherited genetic variants that have yet to be identified. Previous genome-wide linkage studies (GWLSs) have identified a new loci postulated to contain novel CRC risk genes amongst affected families carrying no identifiable mutations in any of the known susceptibility genes for familial CRC syndromes. To undertake a new GWLS, we recruited members from 54 non-syndromic families from Australia and Spain where at least two first-degree relatives were affected by CRC. We used single-nucleotide polymorphism arrays to genotype 98 concordant affected relative pairs that were informative for linkage analyses. We tested for genome-wide significance (GWS) for linkage to CRC using a quantile statistic method, and we found that GWS was achieved at the 5% level. Independently, using the PSEUDO gene-dropping algorithm, we also found that GWS for linkage to CRC was achieved (P=0.02). Merlin non-parametric linkage analysis revealed significant linkage to CRC for chromosomal region 10p15.3–p15.1 and suggestive linkage to CRC for regions on 14q and 9q. The 10p15.3–p15.1 has not been reported to be linked to hereditary CRC in previous linkage studies, but this region does harbour the Kruppel-like factor 6 (KLF6) gene that is known to be altered in common CRC. Further studies aimed at localising the responsible genes, and characterising their function will give insight into the factors responsible for susceptibility in such families, and perhaps shed further light on the mechanisms of CRC development.
doi:10.1038/ejhg.2011.149
PMCID: PMC3234517  PMID: 21829229
colorectal cancer; linkage; 10p; 14q; 9q
22.  Genome-wide linkage using the Social Responsiveness Scale in Utah autism pedigrees 
Molecular Autism  2010;1:8.
Background
Autism Spectrum Disorders (ASD) are phenotypically heterogeneous, characterized by impairments in the development of communication and social behaviour and the presence of repetitive behaviour and restricted interests. Dissecting the genetic complexity of ASD may require phenotypic data reflecting more detail than is offered by a categorical clinical diagnosis. Such data are available from the Social Responsiveness Scale (SRS) which is a continuous, quantitative measure of social ability giving scores that range from significant impairment to above average ability.
Methods
We present genome-wide results for 64 multiplex and extended families ranging from two to nine generations. SRS scores were available from 518 genotyped pedigree subjects, including affected and unaffected relatives. Genotypes from the Illumina 6 k single nucleotide polymorphism panel were provided by the Center for Inherited Disease Research. Quantitative and qualitative analyses were done using MCLINK, a software package that uses Markov chain Monte Carlo (MCMC) methods to perform multilocus linkage analysis on large extended pedigrees.
Results
When analysed as a qualitative trait, linkage occurred in the same locations as in our previous affected-only genome scan of these families, with findings on chromosomes 7q31.1-q32.3 [heterogeneity logarithm of the odds (HLOD) = 2.91], 15q13.3 (HLOD = 3.64), and 13q12.3 (HLOD = 2.23). Additional positive qualitative results were seen on chromosomes 6 and 10 in regions that may be of interest for other neuropsychiatric disorders. When analysed as a quantitative trait, results replicated a peak found in an independent sample using quantitative SRS scores on chromosome 11p15.1-p15.4 (HLOD = 2.77). Additional positive quantitative results were seen on chromosomes 7, 9, and 19.
Conclusions
The SRS linkage peaks reported here substantially overlap with peaks found in our previous affected-only genome scan of clinical diagnosis. In addition, we replicated a previous SRS peak in an independent sample. These results suggest the SRS is a robust and useful phenotype measure for genetic linkage studies of ASD. Finally, analyses of SRS scores revealed linkage peaks overlapping with evidence from other studies of neuropsychiatric diseases. The information available from the SRS itself may, therefore, reveal locations for autism susceptibility genes that would not otherwise be detected.
doi:10.1186/2040-2392-1-8
PMCID: PMC2913945  PMID: 20678250
23.  Age-At-Onset Linkage Analysis in Caribbean Hispanics with Familial Late-Onset Alzheimer’s Disease 
Neurogenetics  2007;9(1):51-60.
The aim of the study was to identify chromosomal regions containing putative genetic variants influencing age-at-onset in familial late-onset Alzheimer’s disease. Data from a genome-wide scan that included genotyping of APOE was analyzed in 1,161 individuals from 209 families of Caribbean Hispanic ancestry with a mean age-at-onset of 73.3 years multiply affected by late-onset Alzheimer’s disease. Two-point and multipoint analyses were conducted using variance component methods from 376 microsatellite markers with an average inter-marker distance of 9.3 cM. Family-based test of association were also conducted for the same set of markers. Age-at-onset of symptoms among affected individuals was used as the quantitative trait. Our results showed that the presence of APOE-ε4 lowered the age-at-onset by three years. Using linkage analysis strategy, the highest LOD scores were obtained using a conservative definition of LOAD at 5q15 (LOD 3.1) 17q25.1 (LOD=2.94) and 14q32.12 (LOD=2.36) and 7q36.3 (LOD=2.29) in covariate adjusted models that included APOE-ε4. Both linkage and family-based association identified 17p13 as a candidate region. In addition, family-based association analysis showed markers at 12q13 (p=0.00002), 13q (p=0.00043) and 14q23 (p=0.00046) to be significantly associated with age at onset. The current study supports the hypothesis that there are additional genetic loci that could influence age-at-onset of late onset Alzheimer’s disease. The novel loci at 5q15, 17q25.1, 13q and 17p13, and the previously reported loci at 7q36.3, 12q13, 14q23 and 14q32 need further investigation.
doi:10.1007/s10048-007-0103-3
PMCID: PMC2701253  PMID: 17940814
Alzheimer’s disease; age-at-onset; linkage analysis; family-based association analysis; APOE
24.  Otitis media: a genome-wide linkage scan with evidence of susceptibility loci within the 17q12 and 10q22.3 regions 
BMC Medical Genetics  2009;10:85.
Background
Otitis media (OM) is a common worldwide pediatric health care problem that is known to be influenced by genetics. The objective of our study was to use linkage analysis to map possible OM susceptibility genes.
Methods
Using a stringent diagnostic model in which only those who underwent tympanostomy tube insertion at least once for recurrent/persistent OM are considered affected, we have carried out a genome-wide linkage scan using the 10K Affymetrix SNP panel. We genotyped 403 Caucasian families containing 1,431 genotyped individuals and 377 genotyped affected sib pairs, and 26 African American families containing 75 genotyped individuals and 27 genotyped affected sib pairs. After careful quality control, non-parametric linkage analysis was carried out using 8,802 SNPs.
Results
In the Caucasian-only data set, our most significant linkage peak is on chromosome 17q12 at rs226088 with a p-value of 0.00007. Other peaks of potential interest are on 10q22.3 (0.00181 at rs1878001), 7q33 (0.00105 at rs958408), 6p25.1 (0.00261 at rs554653), and 4p15.2 (0.00301 at rs2133507). In the combined Caucasian and African American dataset, the 10q22.3 peak becomes more significant, with a minimal p-value of 0.00026 at rs719871. Family-based association testing reveals signals near previously implicated genes: 513 kb from SFTPA2 (10q22.3), 48 kb from IFNG (12q14), and 870 kb from TNF (6p21.3).
Conclusion
Our scan does not provide evidence for linkage in the previously reported regions of 10q26.3 and 19q13.43. Our best-supported linkage regions may contain susceptibility genes that influence the risk for recurrent/persistent OM. Plausible candidates in 17q12 include AP2B1, CCL5, and a cluster of other CCL genes, and in 10q22.3, SFTPA2.
doi:10.1186/1471-2350-10-85
PMCID: PMC2751750  PMID: 19728873
25.  Homozygosity by descent mapping of blood pressure in the Old Order Amish: evidence for sex specific genetic architecture 
BMC Genetics  2007;8:66.
Background
High blood pressure is a well established risk factor for morbidity and mortality acting through heart disease, stroke and cardiovascular disease. Genome wide scans have linked regions of nearly every human chromosome to blood pressure related traits. We have capitalized on beneficial qualities of the Old Order Amish of Lancaster, PA, a closed founder population with a relatively small number of founders, to perform a genome wide homozygosity by descent mapping scan. Each individual in the study has a non zero probability of consanguinity. Systolic and diastolic blood pressures are shown to have appreciable dominance variance components.
Results
Areas of two chromosomes were identified as suggestive of linkage to SBP and 5 areas to DBP in either the overall or sex specific analyses. The strongest evidence for linkage in the overall sample was to Chromosome 18q12 (LOD = 2.6 DBP). Sex specific analyses identified a linkage on Chromosome 4p12-14 (LOD in men only = 3.4 SBP). At Chromosome 2q32-33, an area where we previously reported significant evidence for linkage to DBP using a conventional identity by descent approach, the LOD was 1.4; however an appreciable sex effect was observed with men accounting for most of the linkage (LOD in men only = 2.6).
Conclusion
These results add evidence to a sex specific genetic architecture to blood pressure related traits, particularly in regions of linkage on chromosome 2, 4 and 18.
doi:10.1186/1471-2156-8-66
PMCID: PMC2071912  PMID: 17908314

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