Multipoint LOD Score Research Articles

Genomic screen for loci associated with alcohol dependence in Mission Indians.

Alcohol dependence is a leading cause of morbidity and mortality in Native Americans, yet biological factors underlying the disorder in this ethnic group remain elusive. This study's aims were to map susceptibility loci for DSM-III-R alcohol dependence and two narrower alcohol-related phenotypes in Mission Indian families. Each participant gave a blood sample and completed an interview using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) that was used to make alcohol dependence diagnoses and the narrower phenotypes of withdrawal, and drinking severity. Genotypes were determined for a panel 791 microsatellite polymorphisms. Analyses of multipoint variance component LOD scores for the dichotomous DSM-III-R phenotype revealed no peak LOD scores that exceeded 2.0 at any chromosome location. Two chromosomes, 4 and 12, had peak LOD scores that exceeded 2 for the alcohol use severity phenotype and three chromosomes 6, 15, 16 were found to have peaks with LOD scores that exceeded 2 for the withdrawal phenotype. Evidence for linkage to chromosomes 4 and 15, and 16 have been reported previously for alcohol related phenotypes whereas no evidence has as yet been reported for chromosomes 6 and 12. Combined linkage and association analysis suggest that alcohol dehydrogenase 1B gene polymorphisms are partially responsible for the linkage result on chromosome 4 in this population. These results corroborate the importance of several chromosomal regions highlighted in prior segregation studies in alcoholism and further identify new regions of the genome that may be unique to either the restricted phenotypes evaluated or this population of Mission Indians.

Linkage analysis in bipolar pedigrees adds support for a susceptibility locus on 21q22.

Several studies provide suggestive evidence of a susceptibility locus for bipolar disorder at chromosome 21q22-23. In an attempt to replicate these findings, we have analyzed linkage to 11 polymorphic markers from this region in 18 Bulgarian pedigrees with affective disorder. Two-point linkage analysis under assumption of homogeneity and a dominant model with reduced penetrance produced modest positive values for some of the markers tested under a 'narrow' phenotype definition, including bipolar I and II, and schizoaffective disorder. The maximum two-point score (lod=1.76, theta=0.00) was at marker D21S1919. Non-parametric linkage analysis under the same phenotype model, yielded positive NPLall values (P<0.05) over the region between markers D21S211 and D21S416, with a peak at D21S1252 (NPL Zall=2.32, P=0.0003). The multipoint lod score (GENEHUNTER) reached a suggestive value for linkage (lod=2.10) also at marker D21S1252. The results under a recessive model were completely negative. These data add to the evidence for the existence of a susceptibility locus for bipolar affective disorder on chromosome 21q22.

Genomewide Linkage Scan Identifies a Novel Susceptibility Locus for Restless Legs Syndrome on Chromosome 9p

Restless legs syndrome (RLS) is a common neurological disorder that affects 5%-12% of all whites. To genetically dissect this complex disease, we characterized 15 large and extended multiplex pedigrees, consisting of 453 subjects (134 affected with RLS). A familial aggregation analysis was performed, and SAGE FCOR was used to quantify the total genetic contribution in these families. A weighted average correlation of 0.17 between first-degree relatives was obtained, and heritability was estimated to be 0.60 for all types of relative pairs, indicating that RLS is a highly heritable trait in this ascertained cohort. A genomewide linkage scan, which involved >400 10-cM-spaced markers and spanned the entire human genome, was then performed for 144 individuals in the cohort. Model-free linkage analysis identified one novel significant RLS-susceptibility locus on chromosome 9p24-22 with a multipoint nonparametric linkage (NPL) score of 3.22. Suggestive evidence of linkage was found on chromosome 3q26.31 (NPL score 2.03), chromosome 4q31.21 (NPL score 2.28), chromosome 5p13.3 (NPL score 2.68), and chromosome 6p22.3 (NPL score 2.06). Model-based linkage analysis, with the assumption of an autosomal-dominant mode of inheritance, validated the 9p24-22 linkage to RLS in two families (two-point LOD score of 3.77; multipoint LOD score of 3.91). Further fine mapping confirmed the linkage result and defined this novel RLS disease locus to a critical interval. This study establishes RLS as a highly heritable trait, identifies a novel genetic locus for RLS, and will facilitate further cloning and identification of the genes for RLS.

Lipoprotein lipase gene is in linkage with blood pressure phenotypes in Chinese pedigrees.

To elucidate the mechanism of lipid metabolism in the genesis of essential hypertension (EH), we linked blood pressure (BP) phenotypes with the lipoprotein lipase (LPL) gene. Variance component and sib-pair linkage models were used to test the relationship of the polymorphisms in the LPL gene region and EH in 148 Chinese hypertensive families. Linkage evidence with systolic BP (SBP) and diastolic BP (DBP) was observed in a total population of 148 pedigrees with seven flanking microsatellite markers of the LPL gene, with a maximum two-point LOD score of 2.68 and a maximum multipoint LOD score (MLS) of 2.37 for SBP and a maximum MLS of 1.54 for DBP. Suggestive linkage results around this region were also obtained in northern and southern subsets by geographic distribution. In addition, quantitative-transmission/disequilibrium-test analyses showed that there was linkage between DBP and two single nucleotide polymorphisms in the LPL gene. This is the first report of linkage between LPL gene and DBP in the Chinese population. The LPL gene itself might explain our results or the LPL gene region might harbor some genes to explain the observed results to some degree and might contribute to the variation of BP in the Chinese population.

Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism.

Autism/autistic disorder (MIM number 209850) is a complex, largely genetic psychiatric disorder. The authors recently mapped a susceptibility locus for autism to chromosome region 2q24-q33 (MIM number 606053). In the present study, genes across the 2q24-q33 interval were analyzed to identify an autism susceptibility gene in this region. Mutation screening of positional candidate genes was performed in two stages. The first stage involved identifying, in unrelated subjects showing linkage to 2q24-q33, genetic variants in exons and flanking sequence within candidate genes and comparing the frequency of the variants between autistic and unrelated nonautistic subjects. Two single nucleotide polymorphisms (SNPs) that showed evidence for divergent distribution between autistic and nonautistic subjects were identified, both within SLC25A12, a gene encoding the mitochondrial aspartate/glutamate carrier (AGC1). In the second stage, the two SNPs in SLC25A12 were further genotyped in 411 autistic families, and linkage and association tests were carried out in the 197 informative families. Linkage and association were observed between autistic disorder and the two SNPs, rs2056202 and rs2292813, found in SLC25A12. Using either a single affected subject per family or all affected subjects, evidence for excess transmission was found by the Transmission Disequilibrium Test for rs2056202, rs2292813, and a two-locus G*G haplotype. Similar results were observed using TRANSMIT for the analyses. Evidence for linkage was supported by linkage analysis with the two SNPs, with a maximal multipoint nonparametric linkage score of 1.57 and a maximal multipoint heterogeneity lod score of 2.11. Genotype relative risk could be estimated to be between 2.4 and 4.8 for persons homozygous at these loci. A strong association of autism with SNPs within the SLC25A12 gene was demonstrated. Further studies are needed to confirm this association and to decipher any potential etiological role of AGC1 in autism.

Three potential susceptibility loci shown by a genome-wide scan for regions influencing the age at onset of mania.

The age at onset of bipolar disorder is associated with clinical features of the illness, including duration, severity, and pattern of comorbidity with other disorders. Age at onset is familial and heritable, and it correlates inversely with the prevalence of bipolar disorder among relatives. Because age at onset may have utility in resolving the complexity and heterogeneity of the disorder, the authors sought to identify chromosomal loci that harbor the genes influencing this trait. A genome scan of 539 genotyped people in 97 families ascertained for the NIMH Bipolar Disorder Genetics Initiative was performed by using multipoint variance-components linkage analysis. The age at onset of mania was significantly heritable in these families. Three chromosomal regions yielded nonsignificant but suggestive multipoint lod scores greater than 2.5, with the strongest evidence observed at markers D12S1292, GATA31B, and GATA50C, on chromosomes 12p, 14q, and 15q, respectively. Although firm conclusions await an independent replication, these results suggest that three regions of the genome may contain genes influencing the age at onset of mania in bipolar disorder. To the authors' knowledge, these regions have not been implicated previously in risk for the disorder, suggesting that separate sets of genes influence disease susceptibility and the age at which it appears.

A new locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2L) maps to chromosome 12q24.

Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neurological disorders with a prevalence estimated at 1/2500. The axonal form of this disorder is referred to as Charcot-Marie-Tooth type 2 disease (CMT2). Recently, a large Chinese family with CMT2 was found in the Hunan and Hubei provinces of China. The known loci for CMT1A, CMT2D, CMT1B (the same locus is also responsible for CMT2I and CMT2J), CMT2A, CMT2E, and CMT2F were excluded in this family by linkage analysis. A genome-wide screening was then carried out, and the results revealed linkage of CMT2 to a locus at chromosome 12q24. Haplotype construction and analyses localized this novel locus to a 6.8-cM interval between microsatellite markers D12S366 and D12S1611. The maximal two-point LOD score of 6.35 and multipoint LOD score of 8.08 for marker D12S76 at a recombination fraction (theta) of 0 strongly supported linkage to this locus. Thus, CMT2 neuropathy in this family represents a novel genetic entity that we have designated as CMT2L.

Genome screen for a combined bone phenotype using principal component analysis: the Framingham study

Genetic factors substantially contribute to variation in bone mass. There is a controversy as to whether shared genetic factors exist for bone mass at different sites. We hypothesize that using a composite phenotypic score of several correlated bone mass measures may provide complementary results for linkage studies. In the members of 323 pedigrees from the Framingham Osteoporosis Study, bone mineral density (BMD) was measured at the lumbar spine and three femoral sites (Lunar DPX-L), and quantitative ultrasound (QUS) measured at the calcaneus (Hologic Sahara). Data on age, sex, anthropometry, alcohol and caffeine intake, smoking status, physical activity, menopause, and estrogen use (in females) were also obtained. Principal component analyses of BMD and QUS phenotypes were performed in each sex and generation (parents and offspring). The principal component analyses yielded two components, whose loadings were extracted as principal component scores (PC1 and PC2) for each individual, with PC1 explaining up to 66% of the total variation of all bone mass measurements, and PC2 an additional 24%. Principal component analysis of the three femoral BMD measures resulted in one component (PC_hip) that explained 89–91% of the common variation of hip BMD measures. Quantitative genetic analysis (using the variance components method) revealed that both principal component scores were under significant genetic influences (covariate-adjusted heritabilities of PC1, PC2, and PC_hip were 0.66 ± 0.07, 0.44 ± 0.07, and 0.61 ± 0.06, respectively). For PC1, loci of suggestive linkage were identified on chromosomes 1q21.3 and 8q24.3 with the maximum multipoint LOD scores 2.5 and 2.4, respectively. For PC2, multipoint LOD score was 2.1 on 1p36. Suggestive linkage of PC_hip was found on 8q24.3 and 16p13.2 (LODs > 1.9). In conclusion, an approach to linkage analysis using the linear combination of several correlated bone phenotypes suggests that there are chromosomal loci regulating bone mass, with seemingly pleiotropic effects at different skeletal sites.

Homozygous WNT3 Mutation Causes Tetra-Amelia in a Large Consanguineous Family

Tetra-amelia is a rare human genetic disorder characterized by complete absence of all four limbs and other anomalies. We studied a consanguineous family with four affected fetuses displaying autosomal recessive tetra-amelia and craniofacial and urogenital defects. By homozygosity mapping, the disease locus was assigned to chromosome 17q21, with a maximum multipoint LOD score of 2.9 at markers D17S931, D17S1785, D17SS1827, and D17S1868. Further fine mapping defined a critical interval of approximately 8.9 Mb between D17S1299 and D17S797. We identified a homozygous nonsense mutation (Q83X) in the WNT3 gene in affected fetuses of the family. WNT3, a human homologue of the Drosophila wingless gene, encodes a member of the WNT family known to play key roles in embryonic development. The Q83X mutation truncates WNT3 at its amino terminus, suggesting that loss of function is the most likely cause of the disorder. Our findings contrast with the observation of early lethality in mice homozygous for null alleles of Wnt3. To our knowledge, this is the first report of a mutation in a WNT gene associated with a Mendelian disorder. The identification of a WNT3 mutation in tetra-amelia indicates that WNT3 is required at the earliest stages of human limb formation and for craniofacial and urogenital development.

Japanese SCA families with an unusual phenotype linked to a locus overlapping with SCA15 locus.

The authors identified two Japanese spinocerebellar ataxia (SCA) families characterized by postural and action tremor and a very slow progression rate. A genome-wide linkage analysis revealed linkage to chromosome 3p26.1-25.3 with the highest multipoint lod score at D3S3728 (Zmax = 3.31 at theta = 0.00). The candidate region was 14.7 cM flanked by D3S1620 and D3S3691, which was partly overlapping with the locus of SCA15 characterized by pure cerebellar ataxia. Despite the difference in phenotypes, there remains a possibility that the causative gene for these Japanese SCA is allelic to SCA15.

Evidence for linkage between juvenile myoclonic epilepsy-related idiopathic generalized epilepsy and 6p11-12 in Dutch families.

Previous linkage studies provided evidence for juvenile myoclonic epilepsy (JME) susceptibility loci at 6p11-12, HLA-6p21.3 region, 15q14, and 5q34. These results indicate locus heterogeneity or interpopulation differences, thus underlining the importance of replication studies. We describe a replication linkage study of the 6p-q13 region in 18 families ascertained from JME probands of Dutch descent. In the presence of heterogeneity, the definition of the disease status may be crucial, and we therefore used two disease phenotypes: narrow [JME/idiopathic generalized epilepsy (IGE)-"only"] and broad (JME/IGE-plus-fast EEG background activity). We found evidence of linkage at 6p11-12 in multipoint analyses (p < 0.01 in a replication study) for both these disease definitions. Analysis of this region, assuming heterogeneity and autosomal dominant inheritance with a conservative 60% of penetrance, gave a maximum multipoint parametric lod score of 2.07 at D6S1573 for the narrow phenotype and peaked at 2.53 between D6S1623 and D6S1573 for the broad phenotype. The p value for nonparametric linkage reached 0.0013 for the narrow phenotype and 0.0010 for the broad. Significant exclusion (lod score <or=2) was found for the HLA region and for 10 to 30 cM telomeric to HLA. Our results provide evidence for a susceptibility locus for JME/IGE-plus-fast EEG background activity at 6p11-12. Additionally, by using a narrow definition, we were able to confirm previous evidence for a JME-IGE locus at this location.

Linkage to two separate loci in a family with a novel distal myopathy phenotype (MPD3)

We recently described a new type of adult onset distal myopathy (MPD3) with autosomal dominant inheritance. The onset of symptoms is around the age of 30 and the characteristic first symptoms include clumsiness of the hands and stumbling. The thenar and hypothenar muscles are involved at the onset. The disease progressed to the intrinsic muscles of the hands, both anterior and posterior muscle compartments of the lower legs, the forearm muscles, and later to the proximal muscles. Dystrophic changes with rimmed vacuoles were observed in the muscle biopsy. We have performed a genome wide scan here in order to identify the MPD3 locus. Unexpectedly, markers on two distinct chromosomal regions 8p22-q11 and 12q13-q22, provided significant evidence for linkage in this family. Multipoint linkage analyses produced equal maximum multipoint LOD score of 3.01 for both chromosomal regions and haplotype analysis showed a specific haplotype segregating with the disease for both loci. It is thus impossible to distinguish between two loci without additional family material. Two obvious regional candidate genes, encoding muscular proteins became subjects for sequence analyses, the gene for myosin light chain 1 slow-twitch muscle A on 12q13 and the muscle specific exons of ankyrin 1 on 8p11. No mutations were identified in the coding sequence.

Genomewide Linkage Analysis for Internal Carotid Artery Intimal Medial Thickness: Evidence for Linkage to Chromosome 12

Carotid intimal medial thickness (IMT) is a heritable quantitative measure of atherosclerosis. A genomewide linkage analysis was conducted to localize a quantitative-trait locus (QTL) influencing carotid IMT. Carotid IMT was measured in 596 men and 629 women from 311 extended families (1,242 sib pairs) in the Framingham Heart Study Offspring cohort. B-mode carotid ultrasonography was used to define mean IMT of the carotid artery segments. Multipoint variance-component linkage analysis was performed. Evidence for significant linkage to internal carotid artery (ICA) IMT (two-point log odds [LOD] score 4.1, multipoint LOD score 3.4) was found 161 cM from the tip of the short arm of chromosome 12; these results were confirmed using the GENEHUNTER package (multipoint LOD score 4.3). No LOD scores >2.0 were observed for common carotid artery (CCA) IMT. Association analysis of a single-nucleotide-polymorphism variant of SCARB1 (minor allele frequency 0.13), a gene in close proximity to the region of peak linkage, revealed a protective association of the missense variant allele in exon 1 of SCARB1, with decreased ICA IMT compared with subjects homozygous for the common allele. Although the exon 1 variant contributed 2% to overall variation in ICA IMT, there was no significant change in the peak LOD score after adjustment in the linkage analyses. These data provide substantial evidence for a QTL on chromosome 12 influencing ICA IMT and for association of a rare variant of SCARB1, or a nearby locus, with ICA IMT. Because this rare SCARB1 variant does not account for our observed linkage, further investigations are warranted to identify additional candidate-gene variants on chromosome 12 predisposing to atherosclerosis phenotypes and clinical vascular disease.

Spinocerebellar ataxia type 5: clinical and molecular genetic features of a German kindred.

The authors report a German family with autosomal dominant cerebellar ataxia tightly linked to the spinocerebellar ataxia type 5 (SCA5) locus (multipoint lod score 5.76). The phenotype is characterized by a purely cerebellar syndrome with a downbeat nystagmus occurring prior to the development of other features. Imaging studies demonstrated cortical cerebellar atrophy. Progression is slow even in patients with a disease onset during the second decade. The age at onset varies from 15 to 50 years.

Common variants within the interleukin 4 receptor alpha gene (IL4R) are associated with susceptibility to osteoarthritis.

Primary osteoarthritis (OA) is a common late-onset arthritis that demonstrates a complex mode of transmittance with both joint-site and gender-specific heterogeneity. We have previously linkage-mapped an OA susceptibility locus to a 12-cM interval at chromosome 16p12.3-p12.1 in a cohort of 146 affected female sibling-pair families ascertained by total hip replacement (female-THR families), with a maximum multipoint LOD score of 1.7. Despite the low LOD score, we were encouraged to investigate this interval further following the report of a linkage to the same interval in an Icelandic pedigree with an early-onset form of hip OA. Using public databases, we searched the interval for plausible candidates and concluded that the gene encoding the interleukin 4 receptor alpha chain (IL4R) was a particularly strong candidate based on its known role in cartilage homeostasis. We genotyped nine common single nucleotide polymorphisms (SNPs) from within IL4R, including six non-synonymous SNPs, in the 146 probands from our female-THR families (stage 1) and in an independent cohort of 310 female-THR cases (stage 2). We compared allele frequencies with those of 399 age-matched female controls. All individuals were UK Caucasians. The minor alleles of two SNPs demonstrated association in both stages, with the most significant association having a P-value of 0.004 with an odds ratio (OR) of 2.1. These two SNPs defined two associated SNP groups. Inheriting a minor SNP allele from both groups was a particular risk factor (OR=2.4, P=0.0008). Our data suggest that functional variants within the IL4R gene predispose to hip OA in Caucasian females.

A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree.

Familial hypercholesterolemia results from mutations in the low-density lipoprotein (LDL) receptor or apolipoprotein B genes. We have previously reported the identification of a Utah autosomal-dominant hypercholesterolemia pedigree (kindred 1173) that did not show linkage to either of these loci (Hunt et al. 2000). Expansion of the pedigree and increased marker density within the region of interest have resulted in a multipoint LOD score of 9.6 and enabled us to decrease the size of the linked region to approximately 7.5 Mbp. In addition, we were able to identify additional families sharing the same microsatellite haplotype. While all haplotype carriers in kindred 1173 (K1173) are affected, the haplotype carriers within the newly identified families are unaffected, suggesting that the causal mutation in K1173 had occurred after divergence of these pedigrees from a common ancestor. Mutation screening of genes in the region identified a single nucleotide variant (G-->T) present on the K1173 haplotype that was not present on the same haplotype in the other kindreds. This variant results in a D374Y missense change in the gene PCSK9.

The PARK8 Locus in Autosomal Dominant Parkinsonism: Confirmation of Linkage and Further Delineation of the Disease-Containing Interval

Recently, a new locus (PARK8) for autosomal dominant parkinsonism has been identified in one large Japanese family. Linkage has been shown to a 16-cM centromeric region of chromosome 12, between markers D12S1631 and D12S339. We tested 21 white families with Parkinson disease and an inheritance pattern compatible with autosomal dominant transmission for linkage in this region. Criteria for inclusion were at least three affected individuals in more than one generation. A total of 29 markers were used to saturate the candidate region. One hundred sixty-seven family members were tested (84 affected and 83 unaffected). Under the assumption of heterogeneity and through use of an affecteds-only model, a maximum multipoint LOD score of 2.01 was achieved in the total sample, with an estimated proportion of families with linkage of 0.32. This LOD score is significant for linkage in a replication study and corresponds to a P value of.0047. Two families (family A [German Canadian] and family D [from western Nebraska]) reached significant linkage on their own, with a combined maximum multipoint LOD score of 3.33, calculated with an affecteds-only model (family A: LOD score 1.67, P=.0028; family D: LOD score 1.67, P=.0028). When a penetrance-dependent model was calculated, the combined multipoint LOD score achieved was 3.92 (family A: LOD score 1.68, P=.0027; family D: LOD score 2.24, P=.0007). On the basis of the multipoint analysis for the combined families A and D, the 1-LOD support interval suggests that the most likely disease location is between a CA repeat polymorphism on genomic clone AC025253 (44.5 Mb) and marker D12S1701 (47.7 Mb). Our data provide evidence that the PARK8 locus is responsible for the disease in a subset of families of white ancestry with autosomal dominant parkinsonism, suggesting that it could be a more common locus.

Genome-wide linkage scan for loci predisposing to social phobia: evidence for a chromosome 16 risk locus.

Social phobia is a common, sometimes disabling, fear of situations that might entail scrutiny by others. Several anxiety disorders, including social phobia, are genetically influenced. Genetic linkage analysis can provide the means to identify genomic locations harboring susceptibility loci for genetically influenced disorders. Identifying loci for social phobia was the goal of this study. The authors conducted a genome-wide linkage scan, i.e., tested enough genetic markers to query the entire genome, in 17 American pedigrees (163 subjects) ascertained through probands with panic disorder. Several anxiety disorders segregate in these families; diagnoses were based on structured interviews. A total of 422 markers (404 autosomal, 18 on the X chromosome) with an average spacing of less than 10 centimorgans were genotyped. Multipoint lod score and nonparametric (Zlr score) linkage analyses for social phobia were completed with Allegro and Genehunter X software. Evidence for linkage to social phobia for chromosome 16 markers was identified. A Zlr score of 3.41 was observed for chromosome 16 near marker D16S415. The maximum observed lod score was 2.22, also for chromosome 16, between D16S415 and D16S503 (under a model of recessive inheritance). Additional areas of interest were identified on chromosomes 9, 14, and 18. These findings meet conservative criteria for "suggestive" linkage. The gene encoding the norepinephrine transporter protein (SLC6A2) maps to this broad region, making SLC6A2 both a positional and physiological candidate for influencing social phobia risk. To the authors' knowledge, this is the first complete linkage genome scan for this disorder.

A Candidate Region on 11p13 for Systemic Lupus Erythematosus: A Linkage Identified in African-American Families

Systemic Lupus Erythematosus (SLE), a chronic, complex disease, is the prototype for systemic human autoimmune diseases. Although environmental factors are crucial in triggering the condition, twin and family studies, as well as genetic linkage and association studies, have established its strong genetic predisposition. During the past few years, there has been considerable interest in identifying genomic segments linked to SLE through either a whole genome scan or a candidate gene approach. The discoid lupus erythematosus (DLE) skin lesion is one of the major, and discriminating, manifestations in SLE, especially in African American patients. In this study we have identified 58 multiplex families--27 African American, 26 European American, and 5 others--where at least one SLE patient is also reported to be afflicted with DLE. These families were chosen from the collection of families that are part of our ongoing linkage study for SLE. A genome-wide parametric and nonparametric linkage analysis was conducted with 320 markers. Significant evidence of linkage was identified in only one chromosomal location, 11p13, in the African American families. The maximum 2-point linkage was 5.6 in these pedigrees, obtained at a marker located 47 CM away from the pterminal end of chromosome 11. The peak multipoint LOD score of 4.6 was obtained very nearby. The segregation of this gene suggests dominant inheritance. These results reveal an important genetic effect related to discoid rash at 11p13 in African Americans with SLE, and demonstrate, through increasing genetic homogeneity, the power of pedigree stratification to detect linkage in complex diseases.

Ordered subset linkage analysis supports a susceptibility locus for age-related macular degeneration on chromosome 16p12

BackgroundAge-related macular degeneration (AMD) is a complex disorder that is responsible for the majority of central vision loss in older adults living in developed countries. Phenotypic and genetic heterogeneity complicate the analysis of genome-wide scans for AMD susceptibility loci. The ordered subset analysis (OSA) method is an approach for reducing heterogeneity, increasing statistical power for detecting linkage, and helping to define the most informative data set for follow-up analysis. OSA assesses the linkage evidence in subsets of potentially more homogeneous families by rank-ordering family-specific lod scores with respect to trait-associated covariates or phenotypic features. Here, we present results of incorporating five continuous covariates into our genome-wide linkage analysis of 389 microsatellite markers in 62 multiplex families: Body mass index (BMI), systolic (SBP) and diastolic (DBP) blood pressure, intraocular pressure (IOP), and pack-years of cigarette smoking. Chromosome-wide significance of increases in nonparametric multipoint lod scores in covariate-defined subsets relative to the overall sample was assessed by permutation.ResultsUsing a correction for testing multiple covariates, statistically significant lod score increases were observed for two chromosomal regions: 14q13 with a lod score of 3.2 in 28 families with average IOP ≤ 15.5 (p = 0.002), and 6q14 with a lod score of 1.6 in eight families with average BMI ≥ 30.1 (p = 0.0004). On chromosome 16p12, nominally significant lod score increases (p ≤ 0.05), up to a lod score of 2.9 in 32 families, were observed with several covariate orderings. While less significant, this was the only region where linkage evidence was associated with multiple clinically meaningful covariates and the only nominally significant finding when analysis was restricted to advanced forms of AMD. Families with linkage to 16p12 had higher averages of SBP, IOP and BMI and were primarily affected with neovascular AMD. For all three regions, linkage signals at or very near the peak marker have previously been reported.ConclusionOur results suggest that a susceptibility gene on chromosome 16p12 may predispose to AMD, particularly to the neovascular form, and that further research into the previously suggested association of neovascular AMD and systemic hypertension is warranted.