There is strong evidence for a genetic contribution to epilepsy, but it is commonly assumed that this genetic contribution is limited to ‘generalized’ epilepsies, and that most forms of ‘partial’ epilepsy are nongenetic. In a linkage analysis of a single family containing 11 affected individuals, we obtained strong evidence for localization of a gene for partial epilepsy. This susceptibility gene maps to chromosome 10q, with a maximum two–point lod score for D10S192 of 3.99 at θ=0.0. All affected individuals share a single haplotype for seven tightly linked contiguous markers; the maximum lod score for this haplotype is 4.83 at θ=0.0. Key recombinants place the susceptibility locus within a 10 centimorgan interval.

Late-onset Alzheimer's disease (LOAD) is the most common form of dementia in the elderly. The National Institute of Aging-Late Onset Alzheimer's Disease Family Study and the National Cell Repository for Alzheimer's Disease conducted a joint genome-wide association study (GWAS) of multiplex LOAD families (3,839 affected and unaffected individuals from 992 families plus additional unrelated neurologically evaluated normal subjects) using the 610 IlluminaQuad panel. This cohort represents the largest family-based GWAS of LOAD to date, with analyses limited here to the European-American subjects. SNPs near APOE gave highly significant results (e.g., rs2075650, p = 3.2×10⁻⁸¹), but no other genome-wide significant evidence for association was obtained in the full sample. Analyses that stratified on APOE genotypes identified SNPs on chromosome 10p14 in CUGBP2 with genome-wide significant evidence for association within APOE ε4 homozygotes (e.g., rs201119, p = 1.5×10⁻⁸). Association in this gene was replicated in an independent sample consisting of three cohorts. There was evidence of association for recently-reported LOAD risk loci, including BIN1 (rs7561528, p = 0.009 with, and p = 0.03 without, APOE adjustment) and CLU (rs11136000, p = 0.023 with, and p = 0.008 without, APOE adjustment), with weaker support for CR1. However, our results provide strong evidence that association with PICALM (rs3851179, p = 0.69 with, and p = 0.039 without, APOE adjustment) and EXOC3L2 is affected by correlation with APOE, and thus may represent spurious association. Our results indicate that genetic structure coupled with ascertainment bias resulting from the strong APOE association affect genome-wide results and interpretation of some recently reported associations. We show that a locus such as APOE, with large effects and strong association with disease, can lead to samples that require appropriate adjustment for this locus to avoid both false positive and false negative evidence of association. We suggest that similar adjustments may also be needed for many other large multi-site studies. Genetic factors are well-established to play a role in risk of Alzheimer's disease (AD). However, it has been difficult to find genes that are involved in AD susceptibility, other than a small number of genes that play a role in early-onset, high-penetrant disease risk, and the APOE ε4 allele, which increases risk of late-onset disease. Here we use a European-American family-based sample to examine the role of common genetic variants on late-onset AD. We show that variants in CUGBP2 on chromosome 10p, along with nearby variants, are associated with AD in those highest-risk APOE ε4 homozygotes. We have replicated this interaction in an independent sample. CUGBP2 has one isoform that is expressed predominantly in neurons, and identification of such a new risk locus is important because of the severity of AD. We also provide support for recently proposed associated variants (BIN1, CLU, and partly CR1) and show that there are markers throughout the genome that are correlated with APOE. This emphasizes the need to adjust for APOE for such markers to avoid false associations and suggests that there may be confounding for other diseases with similar strong risk loci.

Individuals from families recruited for the Long Life Family Study (LLFS) (n= 4559) were examined and compared to individuals from other cohorts to determine whether the recruitment targeting longevity resulted in a cohort of individuals with better health and function. Other cohorts with similar data included the Cardiovascular Health Study, the Framingham Heart Study, and the New England Centenarian Study. Diabetes, chronic pulmonary disease and peripheral artery disease tended to be less common in LLFS probands and offspring compared to similar aged persons in the other cohorts. Pulse pressure and triglycerides were lower, high density lipids were higher, and a perceptual speed task and gait speed were better in LLFS. Age-specific comparisons showed differences that would be consistent with a higher peak, later onset of decline or slower rate of change across age in LLFS participants. These findings suggest several priority phenotypes for inclusion in future genetic analysis to identify loci contributing to exceptional survival.

In 1994 and 1995, the National Health Interview Survey included a Disability Supplement (NHIS-D) to collect extensive information about disabilities among individuals sampled as part of annual census-based household interview surveys. Here we describe the development and application of operational definitions of mental retardation and developmental disabilities to items in the NHIS-D to estimate prevalence. In our analyses, we estimate the prevalence of mental retardation in the noninstitutionalized population of the United States to be 7.8 people per thousand (.78%); of developmental disabilities, 11.3 people per thousand (1.13%); and the combined prevalence of mental retardation and/or developmental disabilities to be 14.9 per thousand (1.49%). Differences in prevalence estimates for mental retardation and developmental disabilities and among people of various ages are explored.

Telomeres are stretches of thousands of repeated TTAGGG hexanucleotide sequences located at the ends of each chromosome.¹ Telomeres provide an essential protective role for the genetic material, preventing DNA damage response and repair mechanisms from acting on the chromosomal ends with ensuing genome instability. However, telomere sequences, because of their end positions, are not fully replicated during DNA replication and thus become shorter with each cell division. A ribonucleoprotein enzyme complex known as telomerase can elongate or repair these sequences through a reverse transcriptase activity. Overall, telomeres are shorter in somatic than germline cells. In cultured cells, telomere shortening due to repeated cell divisions correlates with cellular aging, or senescence. In cancer cells, telomeres may be longer, owing to increased telomerase activity. Successful aging may depend on a balance of adequate but not excessive telomerase activity.