Gene expression profiling in peripheral blood lymphocytes for major depression: preliminary cues from Chinese discordant sib-pair study

The etiology of major depressive disorder (MDD) involves many factors such as heredity and environment. There are very few MDD-related studies in Chinese population using twin or sib-pairs for depression-control samples. Here we used the microarray approach and compared gene expression profiling of peripheral blood lymphocytes from 6 sib-pairs discordant on lifetime history of MDD. Within sib-pair differentially expressed genes are obvious fewer in the 1st, 2nd, and 5th compared with those in the 3rd, 4th, and 6th sib-pairs. Gene expression pattern of these DEGs distinguished MDD individuals from the normal one in 3rd, 4th, and 6th sib-pair but not in the 1st, 2nd, and 5th pair, suggesting heterogeneity of different sib-pairs and somewhat commonalities among the 3rd, 4th, and 6th sib-pairs. Comprehensive protein interaction network analysis revealed two key genes PTH and FGF2 in a dominant network where the majority of the genes were significantly down-regulated. PTH was significantly down-regulated in all the sib-pairs while FGF2 was in the 3rd, 4th, and 6th sib-pairs. KEGG enrichment analysis of all the DEGs in networks showed that PTH and related genes were significantly enriched in the pathway of parathyroid hormone secretion, synthesis, and action while FGF2 and related genes were significantly enriched in the pathways of cancer and specifically breast cancer. Generally reduced expression of these genes in peripheral blood lymphocytes of MDD individuals implied their functional repression associated with MDD. Pending validation in more samples, the findings in this study provided valuable cues for understanding the potential mechanism of MDD, as well as potential markers for the diagnosis and treatment of depression in the Chinese population.

Linkage disequilibrium connects genetic records of relatives typed with disjoint genomic marker sets

In familial searching in forensic genetics, a query DNA profile is tested against a database to determine whether it represents a relative of a database entrant. We examine the potential for using linkage disequilibrium to identify pairs of profiles as belonging to relatives when the query and database rely on nonoverlapping genetic markers. Considering data on individuals genotyped with both microsatellites used in forensic applications and genome-wide SNPs, we find that ~30-32% of parent–offspring pairs and ~35-36% of sib pairs can be identified from the SNPs of one member of the pair and the microsatellites of the other. The method suggests the possibility of performing familial searches of microsatellite databases using query SNP profiles, or vice versa. It also reveals that privacy concerns arising from computations across multiple databases that share no genetic markers in common entail risks not only for database entrants, but for their close relatives as well.

Genetic analysis of age at onset variation in spinocerebellar ataxia type 2

Objective:To examine heritability of the residual variability of spinocerebellar ataxia type 2 (SCA2) age at onset (AO) after controlling for CAG repeat length.Methods:From 1955 to 2001, dates of birth, CAG repeat lengths, AO, sex, familial inheritances, and clinical manifestations were collected for a large Cuban SCA2 cohort of 382 affected individuals, including 129 parent-child pairs and 69 sibships. Analyses were performed with log-transformed AO in the GENMOD procedure to predict AO using repeat length, taking into account family structure. Because all relationships were first degree, the model was implemented with an exchangeable correlation matrix. Familial correlations were estimated using the Pedigree Analysis Package to control for similarity due to genetic relatedness.Results:For the entire sample, the mutant CAG repeat allele explained 69% of AO variance. When adjusted for pedigree structure, this decreased to 50%. Evidence for imprinting or sex-specific effects of the CAG repeat on AO was not found. For the entire sample, we determined an upper bound for heritability of the residual variance of 33% (p = 0.008). Heritability was higher in sib-sib pairs, especially in female sib-sib pairs, than in parent-child pairs.Conclusions:We established that a large proportion of AO variance in SCA2 was determined by genetic modifiers in addition to CAG repeat length. The genetic structure of heritability of the residual AO variance was surprisingly similar to Huntington disease, suggesting the presence of recessive modifying alleles and possibly X-chromosome–linked modifiers.

MP7: FAMILIES WITH BOTH NON-HODGKIN'S LYMPHOMA (NHL) AND MYELOMA (MM): ANTICIPATION AND MALE TRANSMISSION

Purpose of StudyTo determine whether genetic rather than environmental factors may be responsible for the occurrence of these neoplasms in families.Methods UsedWe interrogated our registry of >700 pedigrees of families (fams) with multiple hematologic malignancies. We identified 31 fams with both NHL and MM in their pedigrees. In 16 pedigrees a parent and child were affected (12 father-child pairs and 4 mother-child pairs). Fifteen affected sib pairs were identified in the 31 fams, 10 same sex pairs and 5 male-female pairs. Six of the 31 pedigrees had only 1 affected pair. More distant relationships were observed in other fams.Summary of ResultsMale transmission was evident in 25 fams and female transmission was observed in 6. NHL and MM cases had at least 1 unaffected generation (gen) between them in 8 pedigrees, and the diseases occurrred in sequential (13 fams) or the same gen in 10 fams. MM was the diagnosis (dx) in the youngest affected gen in 9 pedigrees, NHL in 13 pedigrees and both occurred in the youngest gen in 9 fams. The median age at dx of 29 NHL patients for whom data were available was 55 yrs (range, 20–99 yrs), and the median age at dx of 26 MM cases was 56 yrs (range, 30–82 yrs). Ten of 26 MM patients were <50 years old at dx. The presence or absence of anticipation could be assessed in 15 of the 31 pedigrees. All 15 displayed anticipation in terms of succeeding gens developing NHL or MM at an earlier age than did the previous gens (median −19 yrs, range −6 to −56 yrs).ConclusionsWe demonstrate anticipation in 15 assessible fams with both NHL and MM, a feature of familial MM that we previoiusly reported (Despande HA, et al: Br J Haematol 1998). More advanced, aggressive disease at dx in the youngest gen is another feature of anticipation, and was observed in 9 of 13 fams in which it could be assessed. Demonstration of anticipation in all 15 evaluable fams suggests a genetic basis for the relationship between these two B-cell disorders. The increase of same sex sib pairs among affected sib pairs implicates a locus on a pseudo-autosomal region of the X chromonsome as potentially responsible for this observation, as we have previously reported for Hodgkin's lymphoma (Horwitz M, Wiernik PH, Am J Hum Genet 1999). Myeloma and non-Hodgkin's lymphoma may have common genetic causation; molecular studies of these fams are planned.