James H. Schick

Dissection of Genomewide-Scan Data in Extended Families Reveals a Major Locus and Oligogenic Susceptibility for Age-Related Macular Degeneration

To examine the genetic basis of age-related macular degeneration (ARMD), a degenerative disease of the retinal pigment epithelium and neurosensory retina, we conducted a genomewide scan in 34 extended families (297 individuals, 349 sib pairs) ascertained through index cases with neovascular disease or geographic atrophy. Family and medical history was obtained from index cases and family members. Fundus photographs were taken of all participating family members, and these were graded for severity by use of a quantitative scale. Model-free linkage analysis was performed, and tests of heterogeneity and epistasis were conducted. We have evidence of a major locus on chromosome 15q (GATA50C03 multipoint P=1.98x10-7; empirical P< or =1.0x10-5; single-point P=3.6x10-7). This locus was present as a weak linkage signal in our previous genome scan for ARMD, in the Beaver Dam Eye Study sample (D15S659, multipoint P=.047), but is otherwise novel. In this genome scan, we observed a total of 13 regions on 11 chromosomes (1q31, 2p21, 4p16, 5q34, 9p24, 9q31, 10q26, 12q13, 12q23, 15q21, 16p12, 18p11, and 20q13), with a nominal multipoint significance level of P< or =.01 or LOD > or =1.18. Family-by-family analysis of the data, performed using model-free linkage methods, suggests that there is evidence of heterogeneity in these families. For example, a single family (family 460) individually shows linkage evidence at 8 loci, at the level of P<.0001. We conducted tests for heterogeneity, which suggest that ARMD susceptibility loci on chromosomes 9p24, 10q26, and 15q21 are not present in all families. We tested for mutations in linked families and examined SNPs in two candidate genes, hemicentin-1 and EFEMP1, in subsamples (145 and 189 sib pairs, respectively) of the data. Mutations were not observed in any of the 11 exons of EFEMP1 nor in exon 104 of hemicentin-1. The SNP analysis for hemicentin-1 on 1q31 suggests that variants within or in very close proximity to this gene cause ARMD pathogenesis. In summary, we have evidence for a major ARMD locus on 15q21, which, coupled with numerous other loci segregating in these families, suggests complex oligogenic patterns of inheritance for ARMD.

Pleiotropic Effects of a Chromosome 3 Locus on Speech-Sound Disorder and Reading

Speech-sound disorder (SSD) is a complex behavioral disorder characterized by speech-sound production errors associated with deficits in articulation, phonological processes, and cognitive linguistic processes. SSD is prevalent in childhood and is comorbid with disorders of language, spelling, and reading disability, or dyslexia. Previous research suggests that developmental problems in domains associated with speech and language acquisition place a child at risk for dyslexia. Recent genetic studies have identified several candidate regions for dyslexia, including one on chromosome 3 segregating in a large Finnish pedigree. To explore common genetic influences on SSD and reading, we examined linkage for several quantitative traits to markers in the pericentrometric region of chromosome 3 in 77 families ascertained through a child with SSD. The quantitative scores measured several processes underlying speech-sound production, including phonological memory, phonological representation, articulation, receptive and expressive vocabulary, and reading decoding and comprehension skills. Model-free linkage analysis was followed by identification of sib pairs with linkage and construction of core shared haplotypes. In our multipoint analyses, measures of phonological memory demonstrated the strongest linkage (marker D3S2465, P=5.6 x 10(-5), and marker D3S3716, P=6.8 x 10(-4)). Tests for single-word decoding also demonstrated linkage (real word reading: marker D3S2465, P=.004; nonsense word reading: marker D3S1595, P=.005). The minimum shared haplotype in sib pairs with similar trait values spans 4.9 cM and is bounded by markers D3S3049 and D3S3045. Our results suggest that domains common to SSD and dyslexia are pleiotropically influenced by a putative quantitative trait locus on chromosome 3.

A Whole-Genome Screen of a Quantitative Trait of Age-Related Maculopathy in Sibships from the Beaver Dam Eye Study

Age-related maculopathy (ARM) is a leading cause of visual impairment among the elderly in Western populations. To identify ARM-susceptibility loci, we genotyped a subset of subjects from the Beaver Dam (WI) Eye Study and performed a model-free genomewide linkage analysis for markers linked to a quantitative measure of ARM. We initially genotyped 345 autosomal markers in 325 individuals ( N =263 sib pairs) from 102 pedigrees. Ten regions suggestive of linkage with ARM were observed on chromosomes 3, 5, 6, 12, 15, and 16. Prior to fine mapping, the most significant regions were an 18-cM region on chromosome 12, near D12S1300 ( P =.0159); a region on chromosome 3, near D3S1763, with a P value of .0062; and a 6-cM region on chromosome 16, near D16S769, with a P value of .0086. After expanding our analysis to include 25 additional fine-mapping markers, we found that a 14-cM region on chromosome 12, near D12S346 (located at 106.89 cM), showed the strongest indication of linkage, with a P value of .004. Three other regions, on chromosomes 5, 6, and 15, that were nominally significant at P ≤.01 are also appropriate for fine mapping.

Comparison of three methods for obtaining principal components from family data in genetic analysis of complex disease.

Three multivariate techniques used to derive principal components (PCs) from family data were compared for their ability to model family data and power to detect linkage. Using the simulated data from Genetic Analysis Workshop 12, the five quantitative traits were first adjusted for age, sex, and environmental factors 1 and 2. Then, standard PCs, PCs obtained from between‐family covariance, and PCs obtained from within‐family genetic covariance were derived and subjected to multivariate sib pair linkage analysis. The standard PCs obtained from the overall correlation matrix allowed identification of key features of the true genetic model more readily than did the other methods. For detection of linkage, standard PCs and PCs obtained from the between‐family genetic covariance performed similarly in terms of both power and type 1 error, and both methods performed better than the PCs obtained from within‐family genetic covariance.

Interaction of gender and body mass index (BMI) reveals evidence of linkage for hypertension in the Framingham Heart Study

BackgroundGenetic heterogeneity and complex biologic mechanisms of blood pressure regulation pose significant challenges to the identification of susceptibility loci influencing hypertension. Previous linkage studies have reported regions of interest, but lack consistency across studies. Incorporation of covariates, in particular the interaction between two independent risk factors (gender and BMI) greatly improved our ability to detect linkage.ResultsWe report a highly significant signal for linkage to chromosome 2p, a region that has been implicated in previous linkage studies, along with several suggestive linkage regions.ConclusionWe demonstrate the importance of including covariates in the linkage analysis when the phenotype is complex.

The Genetic Epidemiology of Age-Related Maculopathy

Abstract Age-related maculopathy is a leading cause of blindness in the elderly. It is a major public health issue of increasing importance as populations become older. Currently considered untreatable, it is a complex disease associated with both genetic and environment factors. As currently reviewed, the importance of genetics in the etiology of age-related macular degeneration has been demonstrated by family studies, twin studies and segregation analysis. Ongoing research at the molecular level is endeavoring to isolate genes involved in the pathogenesis of this complex disease with the goal of identifying those individuals who are susceptible to impairment of visual function prior to overt manifestation of disease. The ultimate aim of this research is to identify molecular targets for appropriate and early therapeutic intervention.

Identification of a major locus for age-related cortical cataract on chromosome 6p12-q12 in the Beaver Dam Eye Study

Age-related cataracts are one of the leading causes of visual impairment and blindness among the elderly worldwide. Among age-related cataracts, cortical opacities rank as the second most common type; however, little is known about their molecular pathogenesis or genetics. To identify susceptibility loci for cortical cataracts, we genotyped a subset of families (102 families; n = 224 sib pairs) from the Beaver Dam Eye Study and performed a model-free genome-wide linkage analysis for markers linked to a quantitative measure of cortical opacity. We obtained evidence for linkage at marker D1S1622 on chromosome 1p35 (P < 0.0002) and at marker D6S1053 on 6q12 (P < 0.00008) in the initial scan. Five additional regions on 1q31, 2p24, 2q11, 4q28, and 15q13 that are suggestive of linkage (P < or = 0.01 or logarithm of the likelihood ratio > or = 1.18) were observed. The region on chromosomes 6p12-q12 was selected for fine mapping, and the intermarker distance was reduced to 3 cM by adding 11 markers in the interval between D6S1017 and D6S1021. After fine mapping, significant evidence of linkage remained on chromosome 6p12-q12 at D6S1053 (P < 0.00005). The current genome scan for age-related cortical cataracts may lead to identification of novel genes, because few regions identified in the current scan have previously been implicated in congenital or age-related cataracts.