Familial Concordance Research Articles

Maternal determinants of gestation length in the rhesus monkey.

A gestation length of normal duration and natural delivery at term are considered to be important indicators of a healthy pregnancy, especially given the potentially adverse consequences for neonates of being born premature. While many have assessed the factors influencing gestation length in humans, and there has been considerable interest in the pregnancy duration of domesticated farm animals, this topic has not been re-assessed recently in rhesus monkeys, the most commonly used primate in biomedical research. In older articles, it's gestation length was typically reported to be 165 days, although most authors acknowledged that viable pregnancies could occur out to 180 days. Predicting the normal range of acceptable due dates has important veterinary implications for when to intervene in a prolonged pregnancy. Using archival records from a large, established breeding program, gestation lengths and infant birthweights were analyzed for 408 pregnancies across a 25-year period. The potential influence of maternal factors, including age and parity, was assessed. Familial concordance in gestation length within mother-daughter matrilines was examined, as well as similarity in length across repeat pregnancies for 84 multiparous females. Mean duration from mating to delivery was 168.8 days, longer than reported in most but not all previous articles. Many females birthed successfully at a longer duration that might have prompted consideration of a caesarian delivery. Gestation length for an individual female was fairly stable and significantly correlated across multiple pregnancies. There was not a pronounced transgenerational influence on gestation length even though familial propensities for birthing small and large infants were evident in the female descendants. Typical pregnancy lengths and birthweights are provided as reference norms to assist other breeding programs and to enhance our understanding of the natural reproduction of rhesus macaques that still live in many forested and urban locations across South Asia.

658Familial aggregation of melanoma by anatomic site of occurrence

Abstract Background Evidence is emerging that melanoma has distinct etiologic pathways and subtypes, characterized by factors like anatomic site. For example, older men have more head and neck melanomas, and younger women more leg melanomas. Family history is a strong risk factor and familial risk genes have been identified. We therefore aimed to investigate familial aggregation of melanoma from an etiologic heterogeneity perspective, to determine whether melanoma subtypes aggregate within families. Methods Using population-level linked health data, we examined the extent to which melanomas in first-degree relatives (FDRs) of cases shared the same body site of occurrence. FDR-pairs diagnosed with melanoma were identified using the Western Australian Cancer Registry and genealogical Family Connections System. Site was categorized as head/neck, trunk/arms, or legs. We identified 1,006 pairs of tumours from 677 family pairs and used Chi-Squared tests to evaluate familial aggregation by site. Degrees of etiologic heterogeneity of individual site-pairs were characterized by site concordance odds ratios. Results Familial aggregation by site was statistically significant (P = 0.01). However, only the site pairings of head/neck versus trunk/arms showed strong evidence of familial concordance (OR = 1.7, 95% CI 1.1-1.7). Trends were broadly similar in same-sex pairs. Conclusions Results show modest evidence of familial aggregation of melanoma by site, with overall evidence of aggregation but inconsistent patterns between sites. Key messages Strong etiologic differences in incidence between anatomic sites for age and sex may be more strongly influenced by non-genetic factors, such as familial patterns of sun exposure.

Something Else Going On? Diagnostic Uncertainty in Children with Chronic Pain and Their Parents.

Diagnostic uncertainty, the perceived lack of an accurate explanation of the patient’s health problem, remains relatively unstudied in children. This study examined the prevalence, familial concordance, and correlates of diagnostic uncertainty in children and their parents presenting to a multidisciplinary pain clinic in the United States. One hundred and twenty-six parents and 91 of their children (Mage = 13.93 years, range = 8–18 years) completed a brief three-item measure of diagnostic uncertainty, as well as measures of pain-related distress and functioning. Forty-eight percent of children and 37% of parents believed something else was going on with the child’s pain that doctors had not found out about yet. Across the three items, 66%–77% of children and their parents agreed in their endorsement of diagnostic uncertainty. Parents who believed that something else was going on with their child’s pain had children with higher avoidance of pain-related activities (F = 5.601, p = 0.020) and lower pain willingness (F = 4.782, p = 0.032). Neither parent nor child diagnostic uncertainty was significantly related to the child’s pain-related functioning. Diagnostic uncertainty, particularly in parents, is relevant in the experience of pediatric chronic pain and warrants further investigation as both a risk factor and therapeutic target.

Test-retest & familial concordance of MDD symptoms

Psychopathology research has increasingly sought to study the etiology and treatment of individual symptoms, rather than categorical diagnoses. However, it is unclear whether commonly used measures have adequate psychometric properties for assessing individual symptoms. This study examined the test-retest reliability and familial concordance (an indicator of validity) of the symptoms of Major Depressive Disorder (MDD), a disorder consisting of nine core symptoms, most of which are aggregated (e.g., symptom 7 of the DSM criteria for MDD is worthlessness or guilt). Lifetime MDD symptoms were measured in 504 young adults (237 sibling pairs) using the Structured Clinical Interview for DSM-5 (SCID). Fifty-one people completed a second SCID within three weeks of their first SCID. Results indicated that aggregated and unaggregated symptoms demonstrated moderate to substantial test-retest reliability and generally significant, but slight to fair familial concordance (with the highest familial concordance being for markedly diminished interest or pleasure and its unaggregated components – decreased interest and decreased pleasure). Given the increasing focus on the differential validity of individual MDD symptoms, the present study suggests that interview-based assessments of depression can assess most individual symptoms with adequate levels of reliability and validity.

The Heritability of Breast Cancer among Women in the Nordic Twin Study of Cancer.

Family history is an established risk factor for breast cancer. Although some important genetic factors have been identified, the extent to which familial risk can be attributed to genetic factors versus common environment remains unclear. We estimated the familial concordance and heritability of breast cancer among 21,054 monozygotic and 30,939 dizygotic female twin pairs from the Nordic Twin Study of Cancer, the largest twin study of cancer in the world. We accounted for left-censoring, right-censoring, as well as the competing risk of death. From 1943 through 2010, 3,933 twins were diagnosed with breast cancer. The cumulative lifetime incidence of breast cancer taking competing risk of death into account was 8.1% for both zygosities, although the cumulative risk for twins whose co-twins had breast cancer was 28% among monozygotic and 20% among dizygotic twins. The heritability of liability to breast cancer was 31% [95% confidence interval (CI), 10%-51%] and the common environmental component was 16% (95% CI, 10%-32%). For premenopausal breast cancer these estimates were 27% and 12%, respectively, and for postmenopausal breast cancer 22% and 16%, respectively. The relative contributions of genetic and environmental factors were constant between ages 50 and 96. Our results are compatible with the Peto-Mack hypothesis. Our findings indicate that familial factors explain almost half of the variation in liability to develop breast cancer, and results were similar for pre- and postmenopausal breast cancer We estimate heritability of breast cancer, taking until now ignored sources of bias into account.

Jeavons syndrome – updated review

Summary Introduction. Eyelid myoclonia and absences (ELMA) was first described by Jeavons in 1977 as a separate type of photosensitive epilepsy. Aim and method. The aim is to consider the updated electro-clinical pathophysiology and to discuss terminology, classification and differential diagnosis. The review includes our own research and relevant papers on the subject of Jeavons syndrome (JS). Review and differential diagnosis. Definition: Jeavons syndrome is a generalized idiopathic (genetic) epilepsy syndrome (IGE) characterized by eyelid myoclonia, other seizures (absences, myoclonic and or generalized tonic-clonic) and EEG paroxysms induced by voluntary or on command eye closure, in the light and photosensitivity. Demographical data: The prevalence of JS has been reported to vary from 7.3% to 12.9% among idiopathic generalized epilepsies and 2.5% to 2.7% among all patients with epileptic disorders. Etiology: JS, as is the case for all idiopathic generalized epilepsies, is genetic and the familial preponderance and concordance is high. Pathophysiology: Three factors are important in order for JS to manifest clinically; the genetic predisposition, the voluntary or on command eye closure and the light input. Clinical forms of JS: we have identified four forms of JS; early onset (< 4 years), mild form, classical form and an ELMA-JME form. Diagnosis: the diagnosis of JS is based on the history, clinical observation and provocation and the confirmation with an EEG. Differential diagnosis: is easily made from tics, other idiopathic generalized or focal cryptogenic/symptomatic epilepsies. Conclusion. JS is characterized by unique electro-clinical features evoked by voluntary or on command eye closure in the light and photosensitivity.

Very early-onset inflammatory bowel disease: gaining insight through focused discovery.

The pathogenesis of pediatric inflammatory bowel disease (IBD) is only partially understood. Strong evidence implicates a strong genetic component including high monozygotic twin concordance and familial disease phenotype concordance rates. Genome-wide association studies have identified associations between >160 genetic loci and the risk for developing IBD. The roles of implicated genes are largely immune-mediated, although other functions include cellular migration, oxidative stress, and carbohydrate metabolism. Additionally, growing literature describes monogenic causes of IBD that frequently present as infantile or very early-onset IBD. The interplay between IBD risk single nucleotide polymorphisms and rare genetic variants has yet to be determined. Studying patients with very early-onset IBD may elicit genetic factors that could be applied to broader populations of IBD. This review describes what is known about the genetic causes of very early-onset IBD and genetic strategies that may unravel more of the genetic causes of IBD.

Genetic variant in fragile histidine triad gene (FHIT) and mortality in prostate and breast cancers: Results from the Prostate, Lung, Colon, Ovarian Cancer Screening Trial (PLCO) and Women’s Health Initiative (WHI).

5076 Background: Prostate and breast cancers combined account for over 10% of all cancer deaths each year in the U.S. Previous studies detected familial concordance in prostate and breast cancer-sp...

The Authors reply

The Authors reply

Concordance of Tumor Differentiation Among Brothers with Prostate Cancer

BackgroundGenetic factors seem to be of greater importance in prostate cancer than in other forms of cancer. Studies have suggested familial concordance in survival, but the extent to which that is due to tumor characteristics is not known. ObjectiveWe hypothesized that a brother of an index case with prostate cancer is at particularly increased risk of prostate cancer with the same tumor differentiation as the index case. Design, setting and participantsWe identified 21 930 brothers of index cases with prostate cancer in the Prostate Cancer Data Base Sweden and followed them up for incidence of prostate cancer. Outcome measurements and statistical analysisThe relative risk of Gleason score–specific prostate cancer in the cohort of brothers was estimated by using the standardized incidence ratio (SIR) stratified by Gleason score of the index case. We estimated 95% confidence intervals (CIs) assuming a Poisson distribution. Results and limitationsAmong brothers of index cases with Gleason score 8–10 cancer, the SIR was 2.53 (95% CI, 1.97–3.21) for a Gleason score 2–6 cancer and 4.00 (95% CI, 2.63–5.82) for a Gleason score 8–10 cancer. SIR for Gleason score 2–6 cancer among brothers decreased with time since the date of the index cases’ diagnoses, whereas the risk of Gleason 8–10 cancer increased over time for brothers of index cases with Gleason 8–10 cancer (p for trend = 0.009). ConclusionsBrothers of men with high-grade prostate cancer are at particularly increased risk of high-grade prostate cancer. Likewise, there is a concordance of less malignant prostate cancers within families. These findings may have direct clinical relevance for counseling men with a family history of prostate cancer.

Familial concordance for height and its components: Analyses from the breakthrough generations study

To assess familial resemblance for height, arm span, and components of these, and differences between concordance for short and tall heights. We examined whether female relatives were similar for six anthropometric measurements (height, arm span, leg, trunk and arm length, and leg:trunk length ratio). Subjects were 31,622 related individuals aged 16-102 yr participating in the UK Breakthrough Generations Study. Height and arm span were self-reported, limb and trunk length were measured in a subset (N = 508) by study investigators, and paternal height was reported by the daughter. Data were analyzed using correlations and Poisson regression. Correlation coefficients within families were 0.4 for height, 0.3 for arm span, and 0.5 for leg length, trunk length, leg:trunk ratio, and arm length. Women had a relative risk (RR) of being short (i.e., in the lowest height quintile) of 2.3 (95% confidence interval [CI] = 2.1-2.5) if their mother was short, 2.1 (95% CI = 1.9-2.3) if their father was short, and 3.7 (95% CI = 3.4-4.0) if both parents were short. RRs of being tall (i.e., in the highest height quintile) were 2.3 (95% CI = 2.1-2.5), 2.4 (95% CI = 2.2-2.6), and 4.4 (95% CI = 4.1-4.8) if their mother, father or both were tall, respectively. We have shown, for the first time, that leg:trunk length ratio and arm length aggregate within families. Concordance seemed to be stronger for tall than short heights.

Familial risk and familial survival in prostate cancer

The Swedish Family-Cancer Database has been the major source of population-based prospective data on familial risks on most cancers, including prostate cancer. In the present review, I focus on three lines of family studies with novel results. The covered studies originate from the same database with publication dates spanning a period of somewhat over 3 years. Age-specific hazard ratios (HRs) of incident prostate cancer and fatal prostate cancer were determined according to the number of affected relatives. Cumulative risks for incidence and death were calculated for the various types of families. Finally, data on the familial association of prostate cancer with some other cancers were reviewed. If the father had prostate cancer, the HR for sons was 2.1 and it increased to 17.7 when three brothers were affected. The highest HR (23) was observed for men before age 60 years with three affected brothers. The patterns for fatal familial prostate cancer were similar. Other reviewed sets of data showed evidence for the familial concordance of good and poor survival in prostate cancer. Familial risks were somewhat higher for fatal than for incident prostate cancer, suggesting that fatal prostate cancers may be a genetic subgroup. Considering the high familial risks in fatal prostate cancer, family history remains an important prognostic piece of information useful for clinical genetic counseling. Obviously, preventive measures for at-risk men are needed but these are beyond the present paper. Starting screening before any prostate cancers are diagnosed in a family appears counterproductive.

Familial concordance for age at natural menopause

Existing estimates of the heritability of menopause age have a wide range. Furthermore, few studies have analyzed to what extent familial similarities might reflect shared environment, rather than shared genes. We therefore analyzed familial concordance for age at natural menopause and the effects of shared genetic and environmental factors on this concordance. Participants were 2,060 individuals comprising first-degree relatives, aged 31 to 90 years, and participating in the UK Breakthrough Generations Study. Menopause data were collected using a self-administered questionnaire and analyzed using logistic regression and variance-components models. Women were at an increased risk of early menopause (≤45 y) if their mother (odds ratio, 6.2; P < 0.001) or non-twin sister (odds ratio, 5.5; P < 0.001) had had an early menopause. Likewise, women had an increased risk of late menopause (≥54 y) if their relative had had a late menopause (mother: odds ratio, 6.1; P < 0.01; non-twin sister: odds ratio, 2.3; P < 0.001). Estimated heritability was 41.6% (P < 0.01), with an additional 13.6% (P = 0.02) of the variation in menopause age attributed to environmental factors shared by sisters. We confirm that early menopause aggregates within families and show, for the first time, that there is also strong familial concordance for late menopause. Both genes and shared environment were the source of variation in menopause age. Past heritability estimates have not accounted for shared environment, and thus, the effect of genetic variants on menopause age may previously have been overestimated.

Familial concordance of metabolic syndrome in Korean population—Korean National Health and Nutrition Examination Survey 2005

AimsTo investigate the familial concordance of metabolic syndrome and its components in a nationally representative survey in Korean. MethodsWe used data from the Korean National Health and Nutrition Examination Survey (KNHANES), a nationwide survey examining the general health and nutritional status of the Korean people. We enrolled 1641 married couples and 1527 parents–1342 offspring. ResultsPrevalence of the metabolic syndrome was 17.1% for husbands, 11.7% for wives, 14.3% for parents, and 7.2% for offspring. After adjustment for age, there were strong positive correlations between family members for the metabolic variables. Compared with husbands whose wives did not have metabolic syndrome, adjusted odds ratio in husbands whose wives had metabolic syndrome was 1.43 (95% CI: 1.10–1.87) for the risk of having metabolic syndrome. Similarly, wives whose husbands had metabolic syndrome had 1.41 (95% CI: 1.08–1.84) times higher risk of having metabolic syndrome. Compared with children whose parents did not have metabolic syndrome, adjusted odds ratio in children with at least one parent with the metabolic syndrome was 2.56 (95% CI: 1.09–5.98) for the metabolic syndrome. ConclusionsOur study revealed that there is significant familial concordance for metabolic syndrome and its components in Korean families.

뇌졸중 환자에서 배우자 사이에 뇌혈관 질환의 위험요인 일치성이 있는가? : 예비 연구

혈관 질환 위험인자의 가족력은 이미 잘 알려져 있으며 최근 심혈관 질환의 위험인자를 대상으로 한 연구에서는 가족력 뿐 만 아니라 배우자간의 위험인자 일치성이 있다고 밝혔다. 이는 혈관 질환 위험인자에서의 가족력은 유전적인 이유뿐 만이 아니라 환경적 요인으로 인해서도 발생한 다는 것을 암시한다. 그러나 뇌졸중이 발생한 환자에서 그 배우자간 위험인자의 일치성을 알아본 연구는 없었다. 이 연구는 본 연구를 진행하기 앞서 시행한 연구로서 뇌졸중으로 입원했던 환자를 대상으로 위험인자간의 관련성을 조사해 그 경향성을 파악하고자 하였는데 고혈압의 유무(p=0.025)와 경동맥 내막-중막 두께(r=0.479, p=0.001)에서 의미있는 연관성을 보였으나 나이를 보정하는 경우 의미가 없는 것으로 드러났다. 일반 인구 대상이거나 심혈관질환자가 대상이었던 종전의 연구 결과와는 다른 결과였다. 의미 있는 경향성을 보인 위험인자에 대해서 추후 보다 큰 규모의 연구가 필요할 것이다. Familial concordance of vascular risk factors is well understood and there are many studies about inter-spouse concordance of the risk factors for coronary heart disease. However, there are no studies for inter-spousal relation of the risk factors in cerebrovascular disease patients. We analysed inter-spouse correlation of cerebrovascular risk factors in patients admitted our hospital due to stroke and their spouses. There was statistically significant inter-spouse concordance in the presence of hypertension(p=0.025) and carotid IMT(r=0.479, p=0.001). However, the further age-adjusted analysis revealed no significant result. Differently from the results of previous studie,, the present study shows no significant spousal concordance. Althought there are tendencies of spousal concordance in some risk factors, the age is major determinant.

Familial concordance of breast cancer pathology as an indicator of genotype in multiple-case families

The heterogeneity of multiple case breast cancer families that do not carry mutations in BRCA1 or BRCA2 (non-BRCA1/2 families) poses a challenge to the identification of breast cancer susceptibility genes. The aim of this study was to determine whether intrafamilial concordance in breast cancer pathology could identify subgroups of non-BRCA1/2 families with consistent genotypic features. Invasive breast cancers were reviewed from 84 individuals belonging to 30 multiple-case families; BRCA1 (n = 9), BRCA2 (n = 10), and non-BRCA1/2 (n = 11). Hierarchical cluster analysis based on histopathology and age at first diagnosis was then used to specify three subgroups designated Clusters 1-3. The genomic features of non-BRCA1/2 families were examined by genome wide linkage and FGFR2 SNP genotyping, according to whether they showed cluster-concordant or cluster-mixed familial pathology. The majority of pathogenic BRCA1 mutation carriers (80%) fell into a single cluster. In contrast pathogenic BRCA2 mutation carriers were distributed across all three clusters and within families, cluster groups were also generally mixed. Most non-BRCA1/2 mutation carriers belonged to Cluster 3 (71%). Genome wide linkage data from five non-BRCA1/2 Cluster 3-concordant families were compared with four mixed cluster non-BRCA1/2 families. This revealed a number of distinct linkage peaks, including some regions previously associated with breast cancer susceptibility. The distribution of low risk alleles in FGFR2 was not different between these two subgroups (P = 0.237). The pattern of breast cancer pathology concordance amongst family members may assist the investigation of breast cancer susceptibility in multiple case families.

In Search of Endophenotypes for Suicidal Behavior

In Search of Endophenotypes for Suicidal Behavior

Survival in non-Hodgkin’s lymphoma by histology and family history

Although survival has been studied for various subtypes of non-Hodgkin's lymphoma (NHL), there have been few comprehensive studies to quantify the prognosis, including all specific histologies. The effect of family history on survival in NHL has not been examined. We used the Swedish Family-Cancer Database to estimate hazard ratios in NHL by histology and family history. Using diffuse centroblastic lymphoma as reference (HR 1.0), patients with Waldenström's macroglobulinemia and hairy-cell leukemia had the best survival. Survival advantage was also noted among patients with lymphoplasmacytic lymphoma and different kinds of follicular lymphomas. For T-cell lymphoma, mycosis fungoides showed a favorable prognosis. As for survival by family history, a total of 98 familial cases were noted in our Database with a similar prognosis compared to sporadic cases in both parental and offspring generations. A non-significant familial concordance of either good or poor survival was noted among family members when probands' prognosis was stratified by survival time. Our results provide quantitative prognosis data for patients with NHL according to specific histologies. Patients with a familial NHL had a similar prognosis compared to patients with sporadic disease. The data suggest familial concordance in either good or poor survival among family members.

Is Genetic Background Important in Lung Cancer Survival?

BackgroundIn lung cancer, a patient's survival is poor with a wide variation in survival within the stage of disease. The aim of this study was to investigate the familial concordance in lung cancer survival by means of analyses of pairs with different degrees of familial relationships.MethodsOur population-based Swedish family database included three million families and over 58 100 lung cancer patients. We modelled the proband (parent, sibling, spouse) survival utilizing a multivariate proportional hazard (Cox) model adjusting for possible confounders of survival. Subsequently, the survival in proband's relative (child, sibling, spouse) was analysed with a Cox model.FindingsBy use of Cox modelling with 5 years follow-up, we noted a decreased hazard ratio for death in children with good parental survival (Hazard Ratio [HR] = 0.71, 95% CI = 0.51 to 0.99), compared to those with poor parental survival. Also for siblings, a very strong protective effect was seen (HR = 0.14, 95% CI = 0.030 to 0.65). Finally, in spouses no correlation in survival was found.InterpretationOur findings suggest that genetic factors are important in lung cancer survival. In a clinical setting, information on prognosis in a relative may be vital in foreseeing the survival in an individual newly diagnosed with lung cancer. Future molecular studies enhancing the understanding of the underlying mechanisms and pathways are needed.

Feeding practices in pregnancy and infancy: relationship with the development of overweight and obesity in childhood

The number of overweight children is increasing rapidly, and there is an urgent need to identify the risk factors for obesity, with a view to preventing further increases in prevalence. Experimental studies in animals and preliminary observations in humans suggest that early experience may influence later risk of obesity, but we do not yet understand the extent to which early influences affect individual vulnerability to risk factors acting later in life. In the developed world, few studies have examined whether current variations in maternal diet have long-term effects on children's body composition. Rapid postnatal growth is associated with greater adiposity, but the role of variations in infant diet and the mechanisms involved are not understood, and there may be interactive effects of early diet and growth rate on body composition. Familial concordance in obesity prevalence suggests that the shared food environment is of key importance. Early life may be a time when dietary practices are established that will continue throughout childhood. Further research is needed to gain insight into the evolution of dietary habits in childhood and to determine how these practices influence obesity risk.