Genetic epidemiological study of maternal and paternal transmission of Alzheimer's disease.

Recent evidence for mitochondrial mutations associated with Alzheimers disease (AD) suggests the possibility of maternal transmission of this illness. We investigated this hypothesis by examining, in a variety of ways, the risk of a primary progressive dementia (PPD) in the parents (n = 650) and siblings (n = 1,220) of 325 AD probands. The results did not support maternal transmission in AD: The mothers of AD probands were not at greater risk of PPD than the fathers or the sisters of AD probands; the offspring of affected mothers were not at greater risk than the offspring of affected fathers or families with no affected parent; and, after selecting those proband families with evidence for increased familial loading, such families did not more frequently have affected mothers than fathers. In contrast, the cumulative risk of PPD in fathers of AD probands, while similar to that of mothers, was significantly increased over the brothers of AD probands. In addition, the cumulative risk curve of PPD in the offspring of affected fathers was significantly higher than the offspring of no affected parents. While no evidence for maternal transmission in AD was observed, unexpectedly, we did find evidence of increased paternal transmission.     

Genetic epidemiological study of maternal and paternal transmission of alzheimer's disease

Recent evidence for mitochondrial mutations associated with Alzheimers disease (AD) suggests the possibility of maternal transmission of this illness. We investigated this hypothesis by examining, in a variety of ways, the risk of a primary progressive dementia (PPD) in the parents (n = 650) and siblings (n = 1,220) of 325 AD probands. The results did not support maternal transmission in AD: The mothers of AD probands were not at greater risk of PPD than the fathers or the sisters of AD probands; the offspring of affected mothers were not at greater risk than the offspring of affected fathers or families with no affected parent; and, after selecting those proband families with evidence for increased familial loading, such families did not more frequently have affected mothers than fathers. In contrast, the cumulative risk of PPD in fathers of AD probands, while similar to that of mothers, was significantly increased over the brothers of AD probands. In addition, the cumulative risk curve of PPD in the offspring of affected fathers was significantly higher than the offspring of no affected parents. While no evidence for maternal transmission in AD was observed, unexpectedly, we did find evidence of increased paternal transmission. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:378–382, 1999. © 1999 Wiley-Liss, Inc.     

Late paternity and stillbirth risk

BACKGROUND: The role of paternal ageing on the incidence of some genetic diseases in offspring depends on the hypothesis that spontaneous mutations accumulate due to continuous cell divisions during spermatogenesis. We examined the effect of paternal age on the complex multifactorial character, stillbirth. METHODS: In 3,619,647 Italian singletons born in 1990-1996 we evaluated stillbirth risk as a function of paternal ageing by means of multiple logistic regression models, which included maternal age and family education, as categorical covariates and interactions. The categorical risk was estimated for mothers and fathers beyond threshold ages of 35 and 40 years, respectively. RESULTS: Stillbirth risk increases with paternal ageing in mothers > or =30 years old, and maternal age and family education modify the impact. In families with low education, the risk accounts for odds ratio (OR) 1.015 [95% confidence interval (CI) 1.01-1.02] in mothers aged 30-34 years, and for OR 1.032 (95% CI 1.02-1.04) in mothers aged > or =35 years; in families with higher education the risk accounts for OR 1.008 (95% CI 1.00-1.02) and OR 1.025 (95% CI 1.01-1.04), respectively, in mothers aged 30-34 and > or =35 years. In these latter families, for mothers aged <35 and fathers > or =40 years the risk accounts for OR 1.12 (95% CI 1.00-1.25). CONCLUSIONS: The effect of paternal ageing on stillbirth risk is revealed in mothers aged > or =30 years and is modified by family education. In mothers aged 30-34 years from families with high education, the increase imputable to paternal ageing might be indicative of a genetic component.     

Paternal age and sporadic schizophrenia: evidence for de novo mutations

Schizophrenia is an etiologically heterogeneous syndrome. It has a strong genetic component and exists in clinically indistinguishable familial and nonfamilial (sporadic) forms. A significant role for de novo genetic mutations in genetic schizophrenia vulnerability is suggested by a strong monotonic increase in schizophrenia risk with advancing paternal age. However, an alternative explanation for the paternal age effect in schizophrenia is that childbearing is delayed in fathers who themselves have genetic schizophrenia vulnerability. In this study, we compared paternal birth ages between patient groups with familial (n = 35) and sporadic (n = 68) patients with DSM-IV schizophrenia from an inpatient schizophrenia research unit. If later age of fathering children is related to having some genetic schizophrenia vulnerability, then paternal birth age should be later in familial schizophrenia cases than in sporadic cases, and any association of father's age and schizophrenia risk in offspring would be a spurious finding, unrelated to etiology. However, if de novo mutations cause sporadic schizophrenia, then patients without a family history of schizophrenia would have older fathers than familial patients. We found that patients without a family history of schizophrenia had significantly older fathers (4.7 years) than familial patients; so later childbirth was not attributable to parental psychiatric illness. These findings support the hypothesis that de novo mutations contribute to the risk for sporadic schizophrenia.     

Evaluating the parent-of-origin effect in bipolar affective disorder. Is a more penetrant subtype transmitted paternally?

BACKGROUND: Numerous genetic mechanisms and modes of transmission underlying bipolar affective disorder (BPAD) have been postulated. Recently, the discovery of genomic imprinting and mitochondrial transmission of illness in humans has stimulated study of parent-of-origin effects in the transmission of BPAD. METHODS: We examined a large sample of families from an associated linkage study to search for a possible parent-of-origin effect. Selecting for unilineal families with at least one offspring and/or parent diagnosed with BPAD after structured interview, we conducted three analyses: (1) the rates of illness among mothers and fathers of offspring affected with BPAD; (2) the observed frequency of transmission and rates of illness among maternal and paternal lineages; and (3) the rates of affective illness among offspring of parents affected with BPAD. RESULTS: Our results indicate no significant differences in the rates of illness among mothers and fathers of offspring affected with BPAD. Also, the frequency of transmission and rates of illness among maternal and paternal lineages did not differ significantly. However, the rate of BPAD among the offspring of fathers affected with BPAD was significantly higher than for mothers with the illness. LIMITATIONS: Substantially more women than men, and maternal than paternal relatives were studied - introducing possible gender biases. CONCLUSIONS: These results suggest a possible paternal parent-of-origin effect.     

Maternal smoking does not influence cord serum IgE or IgD concentrations

Increased cord blood IgE concentrations have been related to atopic risk in children, and a previous study reported increased cord blood IgE concentrations in smoking mothers. These associations suggest a relationship between maternal smoking during pregnancy and atopic risk. To evaluate this question, we prospectively studied parental smoking and cord blood IgE and IgD concentrations in a geographically defined group of women belonging to a health maintenance organization. Cord blood samples were obtained from 847 infants born to these women. Cotinine concentrations were measured in 114 cord blood samples to evaluate the veracity of the maternal smoking histories. Smoking during the prenatal period was reported by 144 mothers (17%) and 204 fathers (25%). Decreased birth weight and length were associated with maternal smoking (p less than 0.001 for both), confirming previous studies. Neither maternal nor paternal smoking was found to be associated with IgE level in univariate or multivariate analyses. Maternal and paternal smoking was associated with IgD (p = 0.03 and p = 0.06, respectively) in univariate analysis. In multiple regression analysis controlling for potentially confounding variables, the association between paternal, but not maternal, smoking and IgD was sustained (p = 0.05 and p greater than 0.20, respectively). Our data do not demonstrate that maternal or paternal smoking increases cord blood IgE.     

Parent-of-origin effect in panic disorder

Parent-of-origin effect was examined in a series of 64 pedigrees with panic disorder (PD) under both the narrow and broad diagnostic models. The narrow diagnostic model defined the affected phenotype to include only the "definite" and "probable" forms of PD, whereas the broad diagnostic model included the entire PD symptomatology. The pattern of maternal vs. paternal transmission of disease was analyzed through a number of comparisons. These comparisons were performed first on all pedigrees and then on a subset of "pure" pedigrees including only strictly maternal transmission or strictly paternal transmission of PD. There were no significant differences in the proportion of offspring born to transmitting mothers vs. transmitting fathers under either diagnostic model or pedigree set. When the difference in the sex ratio among affected offspring from both transmission types was considered, only the "pure" pedigree sample under the broad diagnostic model yielded nominally (i.e., not corrected for multiple tests) significant results (P < .05). Also, the comparisons of cumulative lifetime risk for PD between offspring of transmitting mothers and fathers gave some nominally significant results; when affected and unaffected offspring were considered, significant results were observed under the narrow and broad diagnostic models, P < .0005 and P < .05, respectively. These findings must be considered provisional until confirmed by further study.     

Expressed emotion in multiple subsystems of the families of toddlers with depressed mothers

Expressed emotion was examined in families of toddlers (N = 101) whose mothers had experienced major depressive disorder occurring since the child's birth, and contrasted with expressed emotion in demographically comparable families (N = 54) with no history of parental mental disorder to elucidate family systems processes as contributors to child functioning. Both mothers and fathers provided Five-Minute Speech Samples on their child, their spouse, and themselves, and completed measures of marital adjustment, trait affect, relationship quality with their own parents in childhood, and child behavior problems. Maternal-expressed emotion criticism regarding child, self, and spouse was higher in the families with depressed mothers; paternal criticism regarding self and spouse also was higher in the depressed families. Mothers and fathers in the depressed group also differed on relational/ affective features, exhibiting lower marital satisfaction, higher trait negative affect, and more negative childhood relationship representations, relative to the nondepressed group, and mothers reported more child behavior problems. Mediational models were evaluated separately for the different targets of maternal and paternal criticism and child behavior problems, and findings supported both individual parent and spouse contributions as mediators of the relation between depression group status and expressed criticism and child behavior problems. The findings are discussed in terms of the multiple levels of family system influence on negativity in the emotional environment of toddlers of depressed mothers, developmental risk, and the need for family-level interventions.     

Maternal factors in dizygotic twinning: evidence from interracial crosses

In the USA, Blacks have been shown to have a higher incidence of DZ twinning than Whites. We studied maternal and paternal race determinants of the rates of like-sex and unlike-sex twinning using US live-birth certificate data for 1973-78. After adjustment was made for father's race, Black mothers had a higher rate of unlike-sex twinning than White mothers (odds ratio, OR = 1.74, P less than 10(-8]. This maternal race effect persisted after further adjustments were made for maternal age, parity, education, and marital status and did not apply to the rates of like-sex twinning (OR = 1.06). On the other hand, after adjustment was made for mother's race, Black fathers did not have higher rates of unlike-sex (OR = 0.93) or like-sex (OR = 1.11) twinning than White fathers. The study shows that the high rate of DZ twinning in Blacks is associated with maternal race and not paternal race. The data further support the importance of maternal determinants of dizygotic twinning in humans.     

Genetic heterogeneity in catatonic schizophrenia: A family study

In a family study concentrating on 139 probands with chronic DSM-III-R schizophrenia, catatonic type, 83 probands (41 women, 42 men) met the criteria for periodic catatonia and 56 probands (14 women, 42 men) for systematic catatonia according to the Leonhard classification. The reliability and stability of this subclassification were tested by 2 experienced psychiatrists working independently of each other. Both diagnosticians were kept blind as to the probands' family history. The 139 probands had a total of 543 first-degree relatives. Only those hospitalized for schizophrenia were allocated to the group of afflicted family members. Diagnostic reliability was kappa statistic 0.93 and diagnostic stability during catamnesis reached 97% and kappa of 0.93. Life-table analysis revealed that the age-corrected risks were significantly different in periodic and systematic catatonia. In systematic catatonia mothers had a risk of 6.8%, fathers 2%, and randomly selected sibs 3%. In periodic catatonia an excess of homologous psychoses was apparent: There was a risk of 33.7% for mothers, 15.4% for fathers, and 24.4% for sibs. The quota of afflicted parents (33 of 161) was higher than that of sibs (26 of 162). In periodic catatonia, 59% of the families were multiple afflicted with pronounced unilineal vertical transmission. In 10% of the families 3 successive generations suffered from the disease and were treated in hospital. The results of the study led to the following hypotheses: Periodic and systematic catatonia are valid subgroups of DSM-III-R schizophrenia. In systematic catatonia heritability is very low. Periodic catatonia is a familial disorder. Homogeneity of familial psychoses and unilineal vertical transmission with anticipation are consistent with a major gene effect. Periodic catatonia seems to be a promising candidate for molecular genetic evaluation. © 1996 Wiley-Liss, Inc.     

The inclusion of fathers in the empirical investigation of child psychopathology: an update.

This investigation provides an update on the inclusion of fathers in child psychopathology research. Articles published from January 1992 to January 2005 that examined parental contributions to child psychological maladjustment were identified. Each article was coded for child age, parental race, how parent gender was analyzed, type of journal, and year of publication. Overall, results replicated previous reviews (Phares & Compas, 1992), suggesting that fathers continue to be neglected in child psychopathology research. Further analyses revealed (a) higher rates of paternal research involvement as child age increased, (b) studies with a predominantly Caucasian sample included separate analyses for mothers and fathers more frequently than those with predominantly African American samples, (c) paternal research inclusion was higher in clinical compared to developmental psychology journals, and (d) over the past 6 years, more research has included fathers as participants than from the previous 7-year period (1992-1998).     

The Inclusion of Fathers in the Empirical Investigation of Child Psychopathology: An Update

This investigation provides an update on the inclusion of fathers in child psychopathology research. Articles published from January 1992 to January 2005 that examined parental contributions to child psychological maladjustment were identified. Each article was coded for child age, parental race, how parent gender was analyzed, type of journal, and year of publication. Overall, results replicated previous reviews (Phares & Compas, 1992), suggesting that fathers continue to be neglected in child psychopathology research. Further analyses revealed (a) higher rates of paternal research involvement as child age increased, (b) studies with a predominantly Caucasian sample included separate analyses for mothers and fathers more frequently than those with predominantly African American samples, (c) paternal research inclusion was higher in clinical compared to developmental psychology journals, and (d) over the past 6 years, more research has included fathers as participants than from the previous 7-year period (1992–1998).     

A comparative study of parental stress among mothers and fathers of deaf school-age children

This study examined parental stress among mothers and fathers of deaf school-age children (n = 42). Maternal and paternal stress did not significantly differ as measured by the Questionnaire on Resources and Stress-Short Form's (QRS-SF, Friedrich, Greenberg, & Crnic, 1982, 1983) four scales and total score. Correlational findings showed that paternal stress increased as family occupational status and father's educational attainment increased, whereas maternal stress was not significantly related to these variables. Limited correlational findings suggested a relationship between earlier parental use of sign language and present levels of parental stress. Also, maternal stress increases were associated with older aged children. For both mothers and fathers, increased stress was associated with teacher-reported immaturity. Unlike maternal stress, increased paternal stress was correlated with teacher-reported withdrawn behavior, less developed lipreading skills, and lower peer ratings of social acceptance. The study's findings are discussed in the frameworks of differing parental roles, parent and child communication, and the association of a child's socioemotional school behavior and parental stress.     

Presence of atopy in first-degree relatives as a predictor of a female proband's depression: results from the Northern Finland 1966 Birth Cohort

BACKGROUND: Recent investigations suggest a common genetic rather than environmental cause to explain the association between IgE-mediated atopic allergies and depression. OBJECTIVE: Taking into account psychosocial confounding factors, we investigated separately and at the epidemiologic level the effects of maternal, paternal, and sibling atopy on the cumulative incidence of a child's depression. METHODS: We used an unselected, genetically homogenous, general population birth cohort of 12,058 live-born children in Finland. The 31-year prospective follow-up included questionnaire information on atopic disorders of the cohort members' parents and siblings. The probands' own atopic conditions were evaluated by means of skin prick tests, and information on lifetime depression diagnoses was gleaned from postal questionnaires and national hospital discharge registers. Potential confounders were mother's parity, father's social class, maternal smoking during pregnancy, proband's regular daily smoking, and proband's dwelling place. Total variable information was available from 4068 cohort members. RESULTS: Among female probands, the presence of atopy in parents was the strongest predictor for lifetime depression (P <.001), and sibling atopy and parental atopy were the strongest predictors for hospital-treated depression (P =.018 and P =.036, respectively). After controlling for confounders, it was noticed that maternal atopy increased a female proband's risk of lifetime depression up to 1.9-fold (odds ratio, 1.9; 95% CI, 1.1-3.0). The corresponding risk increased over 4-fold if parental-maternal atopy was combined with proband's own atopy. CONCLUSIONS: Our findings suggest that maternal inheritance could be a significant causative factor in the association between atopy and depression of female probands.     

Polymorphisms in the promoter region of catalase gene and essential hypertension

Genetic variations that predispose individuals to complex disorders, such as essential hypertension, may be found in gene coding regions, intronic regions or in gene promoter regions. Most studies have focused on gene variations that result in amino acid substitutions because they result in different isoforms of the protein, presumably resulting in differences in protein properties. Less attention has been placed on the role of intronic or promoter mutations. In this report, we examined two single nucleotide polymorphisms (SNPs) in the catalase (CAT) gene prompter region in a cohort of hypertensive Caucasians and African Americans with a Mass Spec based Homogenous MassEXTEND assay. We found an association when a specific combination of the two promoter SNPs was examined in Caucasians. No association was observed in African Americans. Our data suggest that genetic variations in the promoter region of catalase gene influence the susceptibility to essential hypertension. In addition, the genetic factors that contribute to hypertension maybe different between ethnic groups.     

Down syndrome associated with father's age in Norway.

Records of births in Norway in 1967 to 1978 were examined for evidence of an increased risk of Down syndrome associated with older paternal age. From among some 685 000 total births with known maternal and paternal age, 693 cases of Down syndrome were reported to the Medical Birth Registry of Norway. The effect of paternal age was assessed by classifying fathers as young and old on the basis of several definitions. The effect of maternal age was removed by stratifying the data on single years of mothers' age. When fathers were considered young if they were less than or equal to 49 and old if they were less than or equal to 50, the analysis yielded a statistic for the test of a one-sided hypothesis which was significant at the 0.05 level. There appears to be an increase risk (perhaps 20 to 30%) of Down syndrome associated with older fathers, independent of maternal age effect. If this increase does in fact exist, it is much smaller than the increases in risk associated with advancing maternal age, and because older men contribute a relatively small proportion of total births their contribution to the communal burden of Down syndrome is quite small. However, the finding is of aetiological interest and is the first indication of a significant paternal age effect where control for maternal age has been stringent.     

Parents and collateral relatives of children with pervasive developmental disorders: A family history study

The objective of this study was to see whether, using the family history method, the risk for pervasive developmental disorder (PDD), cognitive impairments, and other psychiatric symptoms is greater in the parents and collateral relatives of probands with PDD compared to a control group. A semistructured family history interview was carried out with the parents of 52 probands with PDD and 33 parents of controls. Rates of cognitive impairments and psychiatric problems were not found more frequently in parents or relatives of PDD probands compared to relatives of controls, but four cases of PDD were reported among the extended families of the PDD probands. The relatives with PDD were related to the probands through the maternal line, possibly suggesting some form of maternal influence on inheritance or reduced penetrance in females with the PDD genotype. © 1995 Wiley-Liss, Inc.     

Excess paternal age in apparently sporadic osteogenesis imperfecta

The objective of this study was to examine whether parental age is associated with the occurrence of apparently sporadic osteogenesis imperfecta (OI). We compared parental age and the joint distribution of maternal and paternal age with expected distributions based on statutory birth records for each year and location of birth. The study included patients with OI based in the United Kingdom. The study was restricted to cases born in England, Wales, and Scotland between 1961 and 1998. Subgroup analysis was by clinical type [Sillence et al., 1979: J Med Genet 16:101-116] and apparent mode of inheritance based on pedigree analysis. Of 730 eligible cases, 357 were apparently sporadic. The mean age of fathers at birth of children with apparently sporadic OI was 0.87 years greater than expected (P = 0.010; 95% confidence interval = 0.21 to 1.54 years). The relative risk was 1.62 for fathers in the highest quintile of paternal age compared with fathers in the lowest quintile. The magnitude of the paternal age excess did not differ significantly between Sillence types (analysis of variance P = 0.534). In sporadic cases, paternal age was 0.51 years greater than expected, given maternal age, year, and location of birth (P = 0.033). In contrast, in familial cases, there was no significant paternal age excess, and paternal age was not significantly different from that expected given maternal age. Increased paternal age is a significant risk factor for sporadic OI. This effect is not accounted for by increasing maternal age. The magnitude of the paternal age excess is small in comparison with that in some other autosomal dominant disorders.     

Lipoprotein(a) as a risk factor for maternal cardiovascular disease mortality in kindreds with familial combined hyperlipidemia or familial hypertriglyceridemia

Most but not all epidemiologic studies have shown that lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular disease (CVD). Lp(a) levels are also strongly genetically influenced. The purpose of this study was to evaluate the association between Lp(a) levels in adult offspring and parental CVD mortality in 61 kindreds with familial forms of hyperlipidemia. The study sample consisted of offspring-parent pairs in which offspring had fasting Lp(a) measurements and parents had 20-year vital status data and standardized cause-of-death classification if deceased. Linear regression analyses, using a robust variance estimator, were performed separately for 241 offspring with known maternal history (114 mothers) and 194 offspring with known paternal history (93 fathers). Maternal history of CVD mortality was significantly (p=0.004) associated with 2.4-fold higher median Lp(a) levels in offspring compared with those with no maternal history, independent of diabetes, lipid-lowering medications and hormone use. No association was observed between paternal CVD mortality and offspring Lp(a) levels (p=0.505). Adjusting for apolipoprotein(a) kringle 4 number did not alter these parent-specific associations. In conclusion, Lp(a) levels in offspring may be associated with maternal but not paternal history of CVD mortality. This parent-specific finding needs to be confirmed in other samples of high-risk families.     

Higher risk of infantile atopic dermatitis from maternal atopy than from paternal atopy

The risk of infantile atopic dermatitis (AD) posed by maternal atopy and paternal atopy, respectively, were compared in the infants from a birth cohort in whom one of the parents had been designated atopic by skin prick testing. Nineteen with atopic mothers were compared with 20 with atopic fathers. AD, other atopic manifestations and potentially influential factors such as breast-feeding were documented prospectively during the first year in all infants. At 3, 6 and 12 month assessments skin prick sensitivity and total serum IgE concentration were determined. Nine of 19 infants with atopic mothers and two of 20 with atopic fathers had AD (P = 0.023) giving a relative risk of 4.7 (95% confidence interval 2.5 to 9.0). Seven of 19 with atopic mothers and none with atopic fathers had AD with onset before 6 months (P = 0.007). When all types of disease evidence (AD, recurrent wheeze and food reactions) were analysed together no significant difference was apparent between the groups. The two groups were found to be well matched with regard to breast-feeding, time of starting cow's milk, solids and egg, sex, month of birth, parental AD and smoking, race, household pets and neonatal IgE concentration. IgE concentrations at each age and the prevalence of skin prick positivity were similar between the groups. Maternal atopy poses a higher risk for infantile AD and paternal atopy. Whether this may be due to genetic or congenital factors or both is uncertain, but clearly the finding is of relevance in the prediction of allergy in childhood.