Genome-wide association studies identify novel loci in rapidly progressive Alzheimer's disease.

INTRODUCTION: Recent data suggest that distinct prion-like amyloid beta and tau strains are associated with rapidly progressive Alzheimer's disease (rpAD). The role of genetic factors in rpAD is largely unknown. METHODS: Previously known AD risk loci were examined in rpAD cases. Genome-wide association studies (GWAS) were performed to identify variants that influence rpAD. RESULTS: We identified 115 pathology-confirmed rpAD cases and 193 clinical rpAD cases, 80% and 69% were of non-Hispanic European ancestry. Compared to the clinical cohort, pathology-confirmed rpAD had higher frequencies of apolipoprotein E (APOE) ε4 and rare missense variants in AD risk genes. A novel genome-wide significant locus (P < 5×10-8 ) was observed for clinical rpAD on chromosome 21 (rs2832546); 102 loci showed suggestive associations with pathology-confirmed rpAD (P < 1×10-5 ). DISCUSSION rpAD constitutes an extreme subtype of AD with distinct features. GWAS found previously known and novel loci associated with rpAD. Highlights Rapidly progressive Alzheimer's disease (rpAD) was defined with different criteria. Whole genome sequencing identified rare missense variants in rpAD. Novel variants were identified for clinical rpAD on chromosome 21.

Founder population-specific weights yield improvements in performance of polygenic risk scores for Alzheimer disease in the Midwestern Amish.

Alzheimer disease (AD) is the most common type of dementia and is estimated to affect 6 million Americans. Risk for AD is multifactorial, including both genetic and environmental risk factors. AD genomic research has generally focused on identification of risk variants. Using this information, polygenic risk scores (PRSs) can be calculated to quantify an individual's relative disease risk due to genetic factors. The Amish are a founder population descended from German and Swiss Anabaptist immigrants. They experienced a genetic bottleneck after arrival in the United States, making their genetic architecture different from the broader European ancestry population. Prior work has demonstrated the lack of transferability of PRSs across populations. Here, we compared the performance of PRSs derived from genome-wide association studies (GWASs) of Amish individuals to those derived from a large European ancestry GWAS. Participants were screened for cognitive impairment with further evaluation for AD. Genotype data were imputed after collection via Illumina genotyping arrays. The Amish individuals were split into two groups based on the primary site of recruitment. For each group, GWAS was conducted with account for relatedness and adjustment for covariates. PRSs were then calculated using weights from the other Amish group. PRS models were evaluated with and without covariates. The Amish-derived PRSs distinguished between dementia status better than the European-derived PRS in our Amish populations and demonstrated performance improvements despite a smaller training sample size. This work highlighted considerations for AD PRS usage in populations that cannot be adequately described by basic race/ethnicity or ancestry classifications.

Visuospatial and Verbal Memory Differences in Amish Individuals With Alzheimer Disease and Related Dementias.

BACKGROUND: Verbal and visuospatial memory impairments are common to Alzheimer disease and Related Dementias (ADRD), but the patterns of decline in these domains may reflect genetic and lifestyle influences. The latter may be pertinent to populations such as the Amish who have unique lifestyle experiences. METHODS: Our data set included 420 Amish and 401 CERAD individuals. Sex-adjusted, age-adjusted, and education-adjusted Z-scores were calculated for the recall portions of the Constructional Praxis Delay (CPD) and Word List Delay (WLD). ANOVAs were then used to examine the main and interaction effects of cohort (Amish, CERAD), cognitive status (case, control), and sex on CPD and WLD Z-scores. RESULTS: The Amish performed better on the CPD than the CERAD cohort. In addition, the difference between cases and controls on the CPD and WLD were smaller in the Amish and Amish female cases performed better on the WLD than the CERAD female cases. DISCUSSION: The Amish performed better on the CPD task, and ADRD-related declines in CPD and WLD were less severe in the Amish. In addition, Amish females with ADRD may have preferential preservation of WLD. This study provides evidence that the Amish exhibit distinct patterns of verbal and visuospatial memory loss associated with aging and ADRD.

Genetic analysis of cognitive preservation in the midwestern Amish reveals a novel locus on chromosome 2.

INTRODUCTION: Alzheimer disease (AD) remains a debilitating condition with limited treatments and additional therapeutic targets needed. Identifying AD protective genetic loci may identify new targets and accelerate identification of therapeutic treatments. We examined a founder population to identify loci associated with cognitive preservation into advanced age. METHODS: Genome-wide association and linkage analyses were performed on 946 examined and sampled Amish individuals, aged 76-95, who were either cognitively unimpaired (CU) or impaired (CI). RESULTS: 12 SNPs demonstrated suggestive association (P≤5×10-4) with cognitive preservation. Genetic linkage analyses identified >100 significant (LOD≥3.3) SNPs, some which overlapped with the association results. Only one locus on chromosome 2 retained significance across multiple analyses. DISCUSSION: A novel significant result for cognitive preservation on chromosome 2 includes the genes LRRTM4 and CTNNA2. Additionally, the lead SNP, rs1402906, impacts the POU3F2 transcription factor binding affinity, which regulates LRRTM4 and CTNNA2.

The genetic architecture of Alzheimer disease risk in the Ohio and Indiana Amish.

Alzheimer disease (AD) is the most common type of dementia and is currently estimated to affect 6.2 million Americans. It ranks as the sixth leading cause of death in the United States, and the proportion of deaths due to AD has been increasing since 2000, while the proportion of many other leading causes of deaths have decreased or remained constant. The risk for AD is multifactorial, including genetic and environmental risk factors. Although APOE ε4 remains the largest genetic risk factor for AD, more than 26 other loci have been associated with AD risk. Here, we recruited Amish adults from Ohio and Indiana to investigate AD risk and protective genetic effects. As a founder population that typically practices endogamy, variants that are rare in the general population may be of a higher frequency in the Amish population. Since the Amish have a slightly lower incidence and later age of onset of disease, they represent an excellent and unique population for research on protective genetic variants. We compared AD risk in the Amish and to a non-Amish population through APOE genotype, a non-APOE genetic risk score of genome-wide significant variants, and a non-APOE polygenic risk score considering all of the variants. Our results highlight the lesser relative impact of APOE and differing genetic architecture of AD risk in the Amish compared to a non-Amish, general European ancestry population.

Family history and perceptions about risk and prevention for chronic diseases in primary care: a report from the family healthware impact trial.

PURPOSE: To determine whether family medical history as a risk factor for six common diseases is related to patients' perceptions of risk, worry, and control over getting these diseases. METHODS: We used data from the cluster-randomized, controlled Family Healthware Impact Trial (FHITr). At baseline, healthy primary care patients reported their perceptions about coronary heart disease, stroke, diabetes, and breast, ovarian, and colon cancers. Immediately afterward, intervention group participants used Family Healthware to record family medical history; this web-based tool stratified familial disease risks. Multivariate and multilevel regression analyses measured the association between familial risk and patient perceptions for each disease, controlling for personal health and demographics. RESULTS: For the 2330 participants who used Family Healthware immediately after providing baseline data, perceived risk and worry for each disease were strongly associated with family history risk, adjusting for personal risk factors. The magnitude of the effect of family history on perceived risk ranged from 0.35 standard deviation for ovarian cancer to 1.12 standard deviations for colon cancer. Family history was not related to perceived control over developing diseases. Risk perceptions seemed optimistically biased, with 48-79% of participants with increased familial risk for diseases reporting that they were at average risk or below. CONCLUSIONS: Participants' ratings of their risk for developing common diseases, before feedback on familial risk, parallels but is often lower than their calculated risk based on family history. Having a family history of a disease increases its salience and does not change one's perceived ability to prevent the disease.

ZMM proteins during meiosis: crossover artists at work.

Faithful segregation of homologous chromosomes (homologs) during meiosis depends on chiasmata which correspond to crossovers between parental DNA strands. Crossover forming homologous recombination takes place in the context of the synaptonemal complex (SC), a proteinaceous structure that juxtaposes homologs. The coordination between molecular recombination events and assembly of the SC as a structure that provides global connectivity between homologs represents one of the remarkable features of meiosis. ZMM proteins (also known as the synapsis initiation complex = SIC) play crucial roles in both processes providing a link between recombination and SC assembly. The ZMM group includes at least seven functionally collaborating, yet structurally diverse proteins: The transverse filament protein Zip1 establishes stable homolog juxtaposition by polymerizing as an integral component of the SC. Zip2, Zip3, and Zip4 likely mediate protein-protein interactions, while Mer3, Msh4, and Msh5 directly promote steps in DNA recombination. This review focuses on recent insights into ZMM functions in yeast meiosis and draws comparisons to ZMM-related proteins in other model organisms.

Sleep-related epilepsy in the A/J mouse.

RATIONALE: Evident seizures during sleep are common in clinical practice but are uncommonly considered in animal models of epilepsy. A previous observation of spontaneous spike-and-wave activity during sleep in several A/J mice (A/J JAX) from Jackson Laboratory (Bar Harbor, ME) prompted this description of the inheritance of epileptic activity. METHODS: Mice from A/J, C57BI/6J (B6), and chromosomal substitutions strains were instrumented to record EEG and EMG activity over time without and with anti-epileptic drugs. Intercrosses were performed using linkage analysis to localize sub-chromosomal regions. RESULTS: Spike-discharge patterns (n = 12 mice) were of average duration of 1.9 seconds at a rate per hour of 17, with an intrinsic frequency of 6.41 Hz and an amplitude of 634.8 microV. Clonic movements were observed in < 10% of the episodes. Episodes were expressed (> 75%) either in slow-wave sleep or in transitions to and from slow-wave sleep. Events were rare in paradoxical sleep. Compared with vehicle, intraperitoneal administration of ethosuximide (150 mg/kg) or diazepam (5 mg/kg) inhibited or eliminated seizure activity, respectively. In contrast, spontaneous spike-and-wave activity was not observed in A/J mice from Harlan National Laboratories (Indianapolis, Ind) or in B6 mice from Jackson Laboratory. In an intercross between A/J JAX and B6 mice, the trait was not present in the first generation. The trait was observed in 2 chromosome-substitution strains, B6.A4 and B6.A7. In the intercross second generation of these chromosome-substitution strains (n = 113), significant linkage was observed to loci on chromosome 4. CONCLUSIONS: This is a sleep-related epilepsy phenotype that exhibits an oligogenic pattern of allelic inheritance.

Sex, not genotype, determines recombination levels in mice.

Recombination, the precise physical breakage and rejoining of DNA between homologous chromosomes, plays a central role in mediating the orderly segregation of meiotic chromosomes in most eukaryotes. Despite its importance, the factors that control the number and placement of recombination events within a cell remain poorly defined. The rate of recombination exhibits remarkable species specificity, and, within a species, recombination is affected by the physical size of the chromosome, chromosomal location, proximity to other recombination events (i.e., chiasma interference), and, intriguingly, the sex of the transmitting parent. To distinguish between simple genetic and nongenetic explanations of sex-specific recombination differences in mammals, we compared recombination in meiocytes from XY sex-reversed and XO females with that in meiocytes from XX female and XY male mice. The rate and pattern of recombination in XY and XO oocytes were virtually identical to those in normal XX females, indicating that sex, not genotype, is the primary determinant of meiotic recombination patterns in mammals.

Variation in human meiotic recombination.

As recently as 20 years ago, there was relatively little information about the number and distribution of recombinational events in human meiosis, and we knew virtually nothing about factors affecting patterns of recombination. However, the generation of a variety of linkage-based genetic mapping tools and, more recently, cytological approaches that enable us to directly visualize the recombinational process in meiocytes, have led to an increased understanding of human meiosis. In this review, we discuss the different approaches used to study meiotic recombination in humans, our understanding of factors that affect the number and location of recombinational events, and clinical consequences of variation in the recombinational process.

Autosomal dominant acute necrotizing encephalopathy maps to 2q12.1-2q13.

In autosomal dominant acute necrotizing encephalopathy (ADANE), apparently healthy children develop necrotizing lesions in their thalami and brainstems in the course of febrile illnesses. We used DNA from affected subjects and obligate carriers to map ADANE to a 6.5Mb region on chromosome 2. Sequencing of four candidate genes in the interval (BCL2L11, ST6GalII, CHT1, and FLJ20019), involved in apoptosis, viral recognition, choline transport, and electron transport, showed no disease causing mutations.

A genome-wide linkage analysis investigating the determinants of blood pressure in whites and African Americans.

Evidence for genomic regions influencing systolic and diastolic blood pressure (BP) were assessed in a whole genome linkage analysis in 211 African American and 160 white families as part of the GenNet network of the National Heart, Lung and Blood Institute-sponsored Family Blood Pressure Program. Multipoint regression and variance components linkage methods were used to analyze 372 polymorphic markers. Statistically compelling evidence for linkage (P values .0057 and .00023, respectively) was found on chromosome 1. Our results support the idea that BP regulation is most likely governed by multiple genetic loci, each with a relatively weak effect on BP in the population at large.

Genetic control of mammalian meiotic recombination. I. Variation in exchange frequencies among males from inbred mouse strains.

Genetic background effects on the frequency of meiotic recombination have long been suspected in mice but never demonstrated in a systematic manner, especially in inbred strains. We used a recently described immunostaining technique to assess meiotic exchange patterns in male mice. We found that among four different inbred strains--CAST/Ei, A/J, C57BL/6, and SPRET/Ei--the mean number of meiotic exchanges per cell and, thus, the recombination rates in these genetic backgrounds were significantly different. These frequencies ranged from a low of 21.5 exchanges in CAST/Ei to a high of 24.9 in SPRET/Ei. We also found that, as expected, these crossover events were nonrandomly distributed and displayed positive interference. However, we found no evidence for significant differences in the patterns of crossover positioning between strains with different exchange frequencies. From our observations of >10,000 autosomal synaptonemal complexes, we conclude that achiasmate bivalents arise in the male mouse at a frequency of 0.1%. Thus, special mechanisms that segregate achiasmate chromosomes are unlikely to be an important component of mammalian male meiosis.

Covariation of synaptonemal complex length and mammalian meiotic exchange rates.

Analysis of recombination between loci (linkage analysis) has been a cornerstone of human genetic research, enabling investigators to localize and, ultimately, identify genetic loci. However, despite these efforts little is known about patterns of meiotic exchange in human germ cells or the mechanisms that control these patterns. Using recently developed immunofluorescence methodology to examine exchanges in human spermatocytes, we have identified remarkable variation in the rate of recombination within and among individuals. Subsequent analyses indicate that, in humans and mice, this variation is linked to differences in the length of the synaptonemal complex. Thus, at least in mammals, a physical structure, the synaptonemal complex, reflects genetic rather than physical distance.