Mapping of QTL influencing saccharin consumption in the selectively bred alcohol-preferring and -nonpreferring rat lines.

The inbred preferring (iP) and nonpreferring (iNP) rat strains were derived from the selectively bred alcohol-preferring (P) and alcohol-nonpreferring (NP) lines. Previously, 381 iP x iNP F2 progeny were generated to identify quantitative trait loci (QTLs) influencing alcohol consumption and preference. Saccharin consumption (ml/48 h) and saccharin intake (ml/kg/day) were also measured in the F2 sample and were significantly correlated with both alcohol consumption and preference (all r > or = .20, p < .0001), suggesting that there might be some QTLs influencing both saccharin and alcohol phenotypes. We have performed a genome screen using F2 animals with extreme saccharin or alcohol consumption to identify QTLs contributing to saccharin-related phenotypes. Lod scores greater than 2.0 were found on chromosomes 3, 16 and 18 in this sample. Additional genotyping was performed in these regions in the full sample of 381 F2 progeny to further characterize these putative QTLs. On chromosome 3, the maximum lod score in the full sample was 2.7 with saccharin consumption. This QTL appears to overlap with a QTL identified for alcohol consumption in the iP and iNP lines and has pleiotropic effects on both phenotypes. Interestingly, this region of rat chromosome 3 is syntenic with mouse chromosome 2, where a QTL influencing alcohol preference has been previously reported. The QTL on chromosome 16 has a maximum lod score of 4.0 with saccharin intake and 2.6 with saccharin consumption. The QTL on chromosome 18 has a maximum lod score of 2.7 with saccharin consumption. Taken together, these data provide the first results of a genome screen for QTLs contributing to saccharin phenotypes in the rat.

Identification of quantitative trait loci influencing alcohol consumption in the high alcohol drinking and low alcohol drinking rat lines.

Selective breeding has been employed to develop high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) rat lines from the heterogeneous N/Nih rat. Within-family selection and a rotational breeding design were used to discourage inbreeding (Li et al, 1993). To identify quantitative trait loci (QTLs) contributing to alcohol consumption, reciprocal HAD and LAD matings in conjunction with F1 intercrosses were used to create 459 F2 progeny. Using selective genotyping of 151 F2 progeny with extreme alcohol consumption scores and a novel least squares method developed by Haley et al (1994), five chromosomal regions (1, 5, 10, 12, and 16) were identified with lod scores greater than 2.0. Genotyping of the entire sample of 459 F2 progeny produced maximum lod scores of 3.5 on chromosome 5, 2.4 on chromosome 10, 4.7 on chromosome 12 and 2.9 on chromosome 16. The evidence of linkage to chromosome 1 diminished substantially to a maximum lod score of 0.5 when all F2 progeny were genotyped. This study is the first genome-wide study for QTLs underlying alcohol consumption that has employed noninbred lines. Further localization of these QTLs will likely provide insight and candidate genes for the study of human alcoholism.

Suggestive evidence of a locus on chromosome 10p using the NIMH genetics initiative bipolar affective disorder pedigrees.

As part of a four-center NIMH Genetics Initiative on Bipolar Disorder, a genome screen using 365 markers was performed on 540 DNAs from 97 families, enriched for affected relative pairs. This is the largest uniformly ascertained and assessed linkage sample for this disease, and includes 232 subjects diagnosed with bipolar I (BPI), 32 with schizo-affective, bipolar type (SABP), 72 with bipolar II (BPII), and 88 with unipolar recurrent depression (UPR). A hierarchical set of definitions of affected status was examined. Under Model I, affected individuals were those with a diagnosis of BPI or SABP, Model II included as affected those fitting Model I plus BPII, and Model III included those fitting Model II plus UPR. This data set was previously analyzed using primarily affected sib pair methods. We report the results of nonparametric linkage analyses of the extended pedigree structure using the program Genehunter Plus. The strongest finding was a lod score of 2.5 obtained on chromosome 10 near the marker D10S1423 with diagnosis as defined under Model II. This region has been previously implicated in genome-wide studies of schizophrenia and bipolar disorder. Other chromosomal regions with lod scores over 1.50 for at least one Model Included chromosomes 8 (Model III), 16 (Model III), and 20 (Model I). Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:18-23, 2000

Comparing two prevalence rates in a two-phase design study.

An epidemiological study often uses a two-phase design to estimate the prevalence rate of a mental disease. In a two-phase design study, the first phase assesses a large sample with an inexpensive screening test, and then the second phase selects a subsample for a more expensive diagnostic evaluation. Furthermore, disease status may not be ascertained for all subjects who are selected for disease verification because some subjects are unable to be clinically assessed, while others may refuse. Since not all screened subjects are selected for diagnostic assessments, there is potential for verification bias. In this paper, we propose the maximum likelihood (ML) and bootstrap methods to correct for verification bias for estimating and comparing the prevalence rates under the missing-at-random (MAR) assumption for the verification mechanism. We also propose a method to test this MAR assumption. Finally, we apply our methods to a large-scale prevalence study of dementia disorders.

Autosomal recessive familial exudative vitreoretinopathy: evidence for genetic heterogeneity.

Two unrelated families with familial exudative vitreoretinopathy (FEVR) show apparent autosomal recessive inheritance rather than the previously reported autosomal dominant or X-linked recessive mode of inheritance. Compared with the other modes of inheritance, the inherited clinical features here include earlier onset (at birth) and a more severe progressive course.

Genomic screen for QTLs underlying alcohol consumption in the P and NP rat lines.

Selective breeding for voluntary alcohol consumption was utilized to establish the alcohol-preferring (P) and alcohol-nonpreferring (NP) rat lines. Inbreeding was initiated after 30 generations of selection and, after 19 generations of inbreeding, 384 F2 intercross progeny were created to identify quantitative trait loci (QTLs) influencing alcohol consumption. We had reported previously a QTL on Chromosome (Chr) 4; additional markers genotyped on Chr 4 have increased the maximum lod score from 8.6 to 9.2. This QTL acts in an additive fashion and continues to account for approximately 11% of the phenotypic variability. The 95% confidence interval is 12.5 cM and includes the candidate gene, neuropeptide Y. Subsequent to the identification of the QTL on Chr 4, a genome scan was completed to identify additional QTLs influencing alcohol consumption. A lod score of 2.5 was obtained on Chr 3, syntenic to a region previously reported for alcohol preference in mice. Analysis of Chr 8 produced a lod score of 2.2 near the dopamine D2 and serotonin 1b receptors, which have been previously reported as candidate genes for alcohol preference. Evidence for linkage to alcohol consumption was not found on any other chromosome. It therefore appears likely that, in addition to the QTL on Chr 4, multiple loci of small to moderate effect, such as those on Chrs 3 and 8, underlie the difference in alcohol consumption in the P/NP lines.

Phenotypic variability in the chromosome 9 ring.

The syndrome associated to the 9 ring is not commonly observed. The first remark was by Kistenmacher (1970) who examined a male. Later observation of other cases has allowed the syndrome to be described, so that it can be said to be characterized by constant signs, such as microcephaly, psychomotor retardation of varying entity and facial dysmorphism corresponding to that observed in 9 p monosomy. The variability of the phenotype has to be compared with the entity of the telomeric deletion, since the clinical outlook, especially the entity of retardation, could be less serious in case of small deletions.