Childhood and adolescence outcomes in offspring to parents with bipolar disorder: the impact of lifetime parental comorbidity, parental sex, and bipolar subtype.

BACKGROUND: Offspring of parents with bipolar disorder have increased risks of their own psychopathology. However, a large-scale survey of psychiatric, somatic, and adverse social outcomes up to adulthood, which could aid in prioritizing and tailoring prevention, is lacking. It also remains to clarify how risks are modified by other parental factors. METHODS: Swedish population registers were linked to compare offspring having (N = 24,788) and not having (N = 247,880) a parent with bipolar disorder with respect to psychiatric diagnoses and psychotropic medication, birth-related and somatic conditions, social outcomes, accidents, suicide attempts, and mortality. Individuals were followed until age 18. We estimated the influence of lifetime parental psychiatric comorbidity, bipolar disorder subtype, and sex on outcomes. RESULTS: Children of parents with bipolar disorder had 2-3 times higher risks of all psychiatric diagnoses, except for bipolar disorder, for which the risk was 11-fold. Significantly increased risks were also found for several somatic conditions, low school grades, criminal behavior, victimization, accidents, and suicidal behavior. Adjusting for lifetime parental psychiatric comorbidity attenuated most associations. Offspring of a parent with bipolar disorder type 2 had statistically significantly higher risks of attention deficit hyperactivity disorder, respiratory tract conditions, and accidents compared with offspring of a parent with bipolar disorder type 1. Offspring of mothers with bipolar disorder had higher risks of several psychiatric diagnoses, respiratory tract conditions, low school grades, and accidents compared with offspring of fathers with bipolar disorder. Having two parents with bipolar disorder entailed the highest risks of psychiatric outcomes in offspring. CONCLUSIONS: Early intervention and family support are particularly warranted for the offspring of a parent with bipolar disorder in the presence of lifetime parental psychiatric comorbidity, when the parent has bipolar disorder type 2, or when the mother or both parents have bipolar disorder.

Shared familial risk factors between autism spectrum disorder and obesity - a register-based familial coaggregation cohort study.

BACKGROUND: Meta-analyses suggest an association between autism spectrum disorder (ASD) and obesity, but the factors underlying this association remain unclear. This study investigated the association between ASD and obesity stratified on intellectual disability (ID). In addition, in order to gain insight into possible shared etiological factors, the potential role of shared familial liability was examined. METHOD: We studied a cohort of 3,141,696 individuals by linking several Swedish nationwide registers. We identified 35,461 individuals with ASD and 61,784 individuals with obesity. Logistic regression models were used to estimate the association between ASD and obesity separately by ID and sex and by adjusting for parental education, psychiatric comorbidity, and psychotropic medication. Potential shared familial etiologic factors were examined by comparing the risk of obesity in full siblings, maternal and paternal half-siblings, and full- and half-cousins of individuals with ASD to the risk of obesity in relatives of individuals without ASD. RESULTS: Individuals with ASD + ID (OR = 3.76 [95% CI, 3.38-4.19]) and ASD-ID (OR = 3.40 [95% CI, 3.23-3.58]) had an increased risk for obesity compared with individuals without ASD. The associations remained statistically significant when adjusting for parental education, psychiatric comorbidity, and medication. Sex-stratified analyses indicated a higher relative risk for males compared with females, with statistically significant interaction effects for ASD-ID, but not for ASD+ID in the fully adjusted model. First-degree relatives of individuals with ASD+ID and ASD-ID had an increased risk of obesity compared with first-degree relatives of individuals without ASD. The obesity risk was similar in second-degree relatives of individuals with ASD+ID but was lower for and ASD-ID. Full cousins of individuals with ASD+ID had a higher risk compared with half-cousins of individuals with ASD+ID). A similar difference in the obesity risk between full cousins and half-cousins was observed for ASD-ID. CONCLUSIONS: Individuals with ASD and their relatives are at increased risk for obesity. The risk might be somewhat higher for males than females. This warrants further studies examining potential common pleiotropic genetic factors and shared family-wide environmental factors for ASD and obesity. Such research might aid in identifying specific risks and underlying mechanisms in common between ASD and obesity.

Association of Intellectual Disability With All-Cause and Cause-Specific Mortality in Sweden.

Importance: Knowledge of the health challenges and mortality in people with intellectual disability (ID) should guide health policies and practices in contemporary society. Objective: To examine premature mortality in individuals with ID. Design, Setting, and Participants: This population-based longitudinal cohort study obtained data from several national health care, education, and population registers in Sweden. Two registers were used to identify individuals with ID: the National Patient Register and the Halmstad University Register on Pupils With Intellectual Disability. Two cohorts were created: cohort 1 comprised young adults (born between 1980 and 1991) with mild ID, and cohort 2 comprised individuals (born between 1932 and 2013) with mild ID or moderate to profound ID; each cohort had matched reference cohorts. Data analyses were conducted between June 1, 2020, and March 31, 2021. Exposures: Mild or moderate to profound ID. Main Outcomes and Measures: The primary outcome was overall (all-cause) mortality, and the secondary outcomes were cause-specific mortality and potentially avoidable mortality. Results: Cohort 1 included 13 541 young adults with mild ID (mean [SD] age at death, 24.53 [3.66] years; 7826 men [57.8%]), and its matched reference cohort consisted of 135 410 individuals. Cohort 2 included 24 059 individuals with mild ID (mean [SD] age at death, 52.01 [16.88] years; 13 649 male individuals [56.7%]) and 26 602 individuals with moderate to profound ID (mean [SD] age at death, 42.16 [21.68] years; 15 338 male individuals [57.7%]); its matched reference cohorts consisted of 240 590 individuals with mild ID and 266 020 with moderate to profound ID. Young adults with mild ID had increased overall mortality risk compared with the matched reference cohort (odds ratio [OR], 2.86; 95% CI, 2.33-3.50), specifically excess mortality in neoplasms (OR, 3.58; 95% CI, 2.02-6.35), diseases of the nervous system (OR, 40.00; 95% CI, 18.43-86.80) and circulatory system (OR, 9.24; 95% CI, 4.76-17.95). Among deaths that were amenable to health care (OR, 7.75; 95% CI, 4.85-12.39), 55% were attributed to epilepsy. In cohort 2, increased risk of overall mortality was observed among both individuals with mild ID (OR, 6.21; 95% CI, 5.79-6.66) and moderate to profound ID (OR, 13.15; 95% CI, 12.52-13.81) compared with the matched reference cohorts. Those with moderate to profound ID had a higher risk in several cause-of-death categories compared with those with mild ID or the matched reference cohort. Adjustment for epilepsy and congenital malformations attenuated the associations. The relative risk of premature death was higher in women (OR, 6.23; 95% CI, 4.42-8.79) than in men (OR, 1.99; 95% CI, 1.53-2.60), but the absolute risk of mortality was similar (0.9% for women vs 0.9% for men). Conclusions and Relevance: This study found excess premature mortality and high risk of deaths with causes that were potentially amenable to health care intervention among people with ID. This finding suggests that this patient population faces persistent health challenges and inequality in health care encounters.

Premature mortality in autism spectrum disorder.

BACKGROUND: Mortality has been suggested to be increased in autism spectrum disorder (ASD). AIMS: To examine both all-cause and cause-specific mortality in ASD, as well as investigate moderating role of gender and intellectual ability. METHOD: Odds ratios (ORs) were calculated for a population-based cohort of ASD probands (n = 27,122, diagnosed between 1987 and 2009) compared with gender-, age- and county of residence-matched controls (n = 2,672,185). RESULTS: During the observed period, 24,358 (0.91%) individuals in the general population died, whereas the corresponding figure for individuals with ASD was 706 (2.60%; OR = 2.56; 95% CI 2.38-2.76). Cause-specific analyses showed elevated mortality in ASD for almost all analysed diagnostic categories. Mortality and patterns for cause-specific mortality were partly moderated by gender and general intellectual ability. CONCLUSIONS: Premature mortality was markedly increased in ASD owing to a multitude of medical conditions.

Obsessive-Compulsive Disorder, Psychosis, and Bipolarity: A Longitudinal Cohort and Multigenerational Family Study.

Obsessive-compulsive disorder (OCD) often co-occurs with psychotic and bipolar disorders; this comorbidity complicates the clinical management of these conditions. In this population-based longitudinal and multigenerational family study, we examined the patterns of comorbidity, longitudinal risks, and shared familial risks between these disorders. Participants were individuals with a diagnosis of OCD (n = 19,814), schizophrenia (n = 58,336), bipolar disorder (n = 48,180), and schizoaffective disorder (n = 14,904) included in the Swedish Patient Register between January 1969 and December 2009; their first-, second-, and third-degree relatives; and population-matched (1:10 ratio) unaffected comparison individuals and their relatives. The Swedish Prescribed Drug Register was used to control for the potential effect of medication in the longitudinal analyses. Individuals with OCD had a 12-fold increased risk of having a comorbid diagnosis of schizophrenia and a 13-fold increased risk of bipolar disorder and schizoaffective disorder. Longitudinal analyses showed that individuals first diagnosed with OCD had an increased risk for later diagnosis of all other disorders, and vice versa. The risk of bipolar disorder was reduced, but not eliminated, when the use of selective serotonin reuptake inhibitors was adjusted for. OCD-unaffected first-, second-, and third-degree relatives of probands with OCD had a significantly increased risk for all 3 disorders; the magnitude of this risk decreased as the genetic distance increased. We conclude that OCD is etiologically related to both schizophrenia spectrum and bipolar disorders. The results have implications for current gene-searching efforts and for clinical practice.

The association between Darier disease, bipolar disorder, and schizophrenia revisited: a population-based family study.

OBJECTIVES: Darier disease is an autosomal dominant skin disorder caused by mutations in the ATPase, Ca++ transporting, cardiac muscle, slow twitch 2 (ATP2A2) gene and previously reported to cosegregate with bipolar disorder and schizophrenia in occasional pedigrees. It is, however, unknown whether these associations exist also in the general population, and the objective of this study was to examine this question. METHODS: We compared a national sample of individuals with Darier disease and their first-degree relatives with matched unexposed individuals from the general population and their first-degree relatives, respectively. To examine risks for bipolar disorder and schizophrenia, risk ratios and 95% confidence intervals (CIs) were estimated using conditional logistic regressions. RESULTS: Individuals with Darier disease had a 4.3 times higher risk of being diagnosed with bipolar disorder (95% CI: 2.6-7.3) and a 2.3 times higher risk of being diagnosed with schizophrenia (95% CI: 1.1-5.2) than matched individuals from the general population. Relatives of individuals with Darier disease had a 1.6 times higher risk of having bipolar disorder (95% CI: 1.1-2.5) than relatives of matched individuals from the general population, but no increased risk of schizophrenia (risk ratio = 0.8, 95% CI: 0.4-1.8). CONCLUSIONS: The association between Darier disease and bipolar disorder is manifest also in the population, and our data suggest that genetic variability within the ATP2A2 gene that causes Darier disease also confers susceptibility for bipolar disorder. The Darier-causing mutations merit additional attention in molecular genetic research on bipolar disorder.

Relative immaturity and ADHD: findings from nationwide registers, parent- and self-reports.

BACKGROUND: We addressed if immaturity relative to peers reflected in birth month increases the likelihood of ADHD diagnosis and treatment. METHODS: We linked nationwide Patient and Prescribed Drug Registers and used prospective cohort and nested case-control designs to study 6-69 year-old individuals in Sweden from July 2005 to December 2009 (Cohort 1). Cohort 1 included 56,263 individuals diagnosed with ADHD or ever used prescribed ADHD-specific medication. Complementary population-representative cohorts provided DSM-IV ADHD symptom ratings; parent-reported for 10,760 9-year-old twins born 1995-2000 from the CATSS study (Cohort 2) and self-reported for 6,970 adult twins age 20-47 years born 1959-1970 from the STAGE study (Cohort 3). We calculated odds ratios (OR:s) for ADHD across age for individuals born in November/December compared to January/February (Cohort 1). ADHD symptoms in Cohorts 2 and 3 were studied as a function of calendar birth month. RESULTS: ADHD diagnoses and medication treatment were both significantly more common in individuals born in November/December versus January/February; peaking at ages 6 (OR: 1.8; 95% CI: 1.5-2.2) and 7 years (OR: 1.6; 95% CI: 1.3-1.8) in the Patient and Prescribed Drug Registers, respectively. We found no corresponding differences in parent- or self-reported ADHD symptoms by calendar birth month. CONCLUSION: Relative immaturity compared to class mates might contribute to ADHD diagnosis and pharmacotherapy despite absence of parallel findings in reported ADHD symptom loads by relative immaturity. Increased clinical awareness of this phenomenon may be warranted to decrease risk for imprecise diagnostics and treatment. We speculate that flexibility regarding age at school start according to individual maturity could reduce developmentally inappropriate demands on children and improve the precision of ADHD diagnostic practice and pharmacological treatment.

Modest familial risks for multiple sclerosis: a registry-based study of the population of Sweden.

Data on familial recurrence rates of complex diseases such as multiple sclerosis give important hints to aetiological factors such as the importance of genes and environment. By linking national registries, we sought to avoid common limitations of clinic-based studies such as low numbers, poor representation of the population and selection bias. Through the Swedish Multiple Sclerosis Registry and a nationwide hospital registry, a total of 28 396 patients with multiple sclerosis were identified. We used the national Multi-Generation Registry to identify first and second degree relatives as well as cousins, and the Swedish Twin Registry to identify twins of patients with multiple sclerosis. Crude and age corrected familial risks were estimated for cases and found to be in the same range as previously published figures. Matched population-based controls were used to calculate relative risks, revealing lower estimates of familial multiple sclerosis risks than previously reported, with a sibling recurrence risk (λs = 7.1; 95% confidence interval: 6.42-7.86). Surprisingly, despite a well-established lower prevalence of multiple sclerosis amongst males, the relative risks were equal among maternal and paternal relations. A previously reported increased risk in maternal relations could thus not be replicated. An observed higher transmission rate from fathers to sons compared with mothers to sons suggested a higher transmission to offspring from the less prevalent sex; therefore, presence of the so-called 'Carter effect' could not be excluded. We estimated the heritability of multiple sclerosis using 74 757 twin pairs with known zygosity, of which 315 were affected with multiple sclerosis, and added information from 2.5 million sibling pairs to increase power. The heritability was estimated to be 0.64 (0.36-0.76), whereas the shared environmental component was estimated to be 0.01 (0.00-0.18). In summary, whereas multiple sclerosis is to a great extent an inherited trait, the familial relative risks may be lower than usually reported.

Klinefelter syndrome and risk of psychosis, autism and ADHD.

BACKGROUND: Schizophrenia, bipolar disorder, autism spectrum disorders and ADHD might be overrepresented in Klinefelter syndrome, but previous investigations have yielded inconclusive results. METHODS: We compared a national sample of 860 Klinefelter patients in Sweden with 86 000 matched population controls. To assess the risks of schizophrenia, bipolar disorder, autism spectrum disorder and ADHD in Klinefelter patients, we estimated odds ratios and 95% confidence intervals using conditional logistic regressions. RESULTS: Klinefelter patients had almost four times higher risks of schizophrenia, odds ratio (OR) = 3.6, 95% confidence interval (CI) 2.0-6.7 and bipolar disorder (OR = 3.8, CI 1.8-7.6) and about six times higher risk of autism spectrum disorder (OR = 6.2, CI 4.0-9.4) and ADHD (OR = 5.6, CI 4.0-7.8). CONCLUSIONS: The risk of psychosis, autism and ADHD is increased in Klinefelter patients. These findings indicate an X chromosome-related factor in the etiology of the studied psychiatric disorders, and may also have implications for treatment of patients with Klinefelter syndrome.

Population-based, multigenerational family clustering study of obsessive-compulsive disorder.

IMPORTANCE: Controlled family studies have consistently found that obsessive-compulsive disorder (OCD) aggregates in families but have typically relied on samples recruited from specialist clinics. Furthermore, previous studies could not disentangle genetic from environmental factors contributing to the observed familiality. OBJECTIVE: To provide unbiased estimates of familial risk for and heritability of OCD at the population level. DESIGN AND SETTING: Population-based, multigenerational, case-control family and twin studies using the Swedish National Patient Register, Multi-Generation Register, and Twin Register. PARTICIPANTS: All individuals diagnosed as having OCD between January 1, 1969, and December 31, 2009 (n = 24 768) and all their available first-, second-, and third-degree relatives, as well as nonbiological relatives and matched general population control subjects. Twins (n = 16 383) were included from the population-based Twin Register. MAIN OUTCOME AND MEASURE: The risk for OCD among relatives of OCD probands. RESULTS: The risk for OCD among relatives of OCD probands increased proportionally to the degree of genetic relatedness. The risk for first-degree relatives was significantly higher than that for second- and third-degree and nonbiological relatives. Second-degree relatives had higher risk for OCD than third-degree relatives. Relatives at similar genetic distances had similar risks for OCD, despite different degrees of shared environment. Separate twin modeling analyses confirmed that familial risk for OCD was largely attributable to additive genetic factors (47%; 95% CI, 42%-52%), with no significant effect of shared environment. Nonbiological relatives (spouses or partners who have at least 1 child together) also had an elevated risk for OCD (odds ratio, 2.61; 95% CI, 1.99-3.42). Early-onset probands (3907 individuals; mean age, 13.7 years) had slightly (nonsignificantly) higher familial risk than the total sample, although this was substantially lower than previously reported. There were no significant sex differences in the familial pattern or heritability estimates. CONCLUSIONS AND RELEVANCE: Obsessive-compulsive disorder clusters in families primarily due to genetic factors. Nonshared environmental factors are at least as important. The quest for candidate genes, nonshared environmental risk factors, and their possible correlation or interaction should continue. The finding of possible assortative mating in OCD is intriguing and should be investigated further.

Risk of bipolar disorder and schizophrenia in relatives of people with attention-deficit hyperactivity disorder.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is associated with bipolar disorder and schizophrenia, and it has been suggested that combined bipolar disorder and ADHD is aetiologically distinct from the pure disorders. AIMS: To clarify whether ADHD shares genetic and environmental factors with bipolar disorder and schizophrenia. METHOD: By linking longitudinal Swedish national registers, we identified 61 187 persons with ADHD (the proband group) and their first- and second-degree relatives, and matched them with a control group of people without ADHD and their corresponding relatives. Conditional logistic regression was used to determine the risks of bipolar disorder and schizophrenia in the relatives of the two groups. RESULTS: First-degree relatives of the ADHD proband group were at increased risk of both bipolar disorder (odds ratio (OR) = 1.84-2.54 for parents, offspring and full siblings) and schizophrenia (OR = 1.71-2.22 for parents, offspring and full siblings). The risks of bipolar disorder and schizophrenia among second-degree relatives were substantially lower than among full siblings. CONCLUSIONS: These findings suggest that the co-occurrence of ADHD and bipolar disorder as well as ADHD and schizophrenia is due to shared genetic factors, rather than representing completely aetiologically distinct subsyndromes.

Mental illness, suicide and creativity: 40-year prospective total population study.

We previously demonstrated that patients with schizophrenia or bipolar disorder and their relatives are overrepresented in creative occupations. Here, we use a new dataset with a considerably larger sample of patients (n = 1,173,763) to survey other psychiatric diagnoses and to validate previous findings. The specific aims of this study were to i) investigate if creativity is associated with all psychiatric disorders or restricted to those with psychotic features, and ii) to specifically investigate authors in relationship to psychopathology. We conducted a nested case-control study using longitudinal Swedish total population registries, where the occurrence of creative occupations in patients and their non-diagnosed relatives was compared to that of matched population controls. Diagnoses included were schizophrenia, schizoaffective disorder, bipolar disorder, unipolar depression, anxiety disorders, alcohol abuse, drug abuse, autism, ADHD, anorexia nervosa, and completed suicide. Creative professions were defined as scientific and artistic occupations. Data were analyzed using conditional logistic regression. Except for bipolar disorder, individuals with overall creative professions were not more likely to suffer from investigated psychiatric disorders than controls. However, being an author was specifically associated with increased likelihood of schizophrenia, bipolar disorder, unipolar depression, anxiety disorders, substance abuse, and suicide. In addition, we found an association between creative professions and first-degree relatives of patients with schizophrenia, bipolar disorder, anorexia nervosa, and for siblings of patients with autism. We discuss the findings in relationship to some of the major components of creativity.

Family history of schizophrenia and bipolar disorder as risk factors for autism.

CONTEXT: The clinical and etiologic relation between autism spectrum disorders (ASDs) and schizophrenia is unclear. The degree to which these disorders share a basis in etiology has important implications for clinicians, researchers, and those affected by the disorders. OBJECTIVE: To determine whether a family history of schizophrenia and/or bipolar disorder is a risk factor for ASD. DESIGN, SETTING, AND PARTICIPANTS: We conducted a case-control evaluation of histories of schizophrenia or bipolar disorder in first-degree relatives of probands in 3 samples­population registers in Sweden, Stockholm County (in Sweden), and Israel. Probands met criteria for ASD, and affection status of parents and siblings for schizophrenia and bipolar disorder were established. RESULTS: The presence of schizophrenia in parents was associated with an increased risk for ASD in a Swedish national cohort (odds ratio [OR], 2.9; 95% CI, 2.5-3.4) and a Stockholm County cohort (OR, 2.9; 95% CI, 2.0-4.1). Similarly, schizophrenia in a sibling was associated with an increased risk for ASD in a Swedish national cohort (OR, 2.6; 95% CI, 2.0-3.2) and an Israeli conscription cohort (OR, 12.1; 95% CI, 4.5-32.0). Bipolar disorder showed a similar pattern of associations but of lesser magnitude. CONCLUSIONS: Findings from these 3 registers along with consistent findings from a similar study in Denmark suggest that ASD, schizophrenia, and bipolar disorder share common etiologic factors.

Creativity and mental disorder: family study of 300,000 people with severe mental disorder.

BACKGROUND: There is a long-standing belief that creativity is coupled with psychopathology. AIMS: To test this alleged association and to investigate whether any such association is the result of environmental or genetic factors. METHOD: We performed a nested case-control study based on Swedish registries. The likelihood of holding a creative occupation in individuals who had received in-patient treatment for schizophrenia, bipolar disorder or unipolar depression between 1973 and 2003 and their relatives without such a diagnosis was compared with that of controls. RESULTS: Individuals with bipolar disorder and healthy siblings of people with schizophrenia or bipolar disorder were overrepresented in creative professions. People with schizophrenia had no increased rate of overall creative professions compared with controls, but an increased rate in the subgroup of artistic occupations. Neither individuals with unipolar depression nor their siblings differed from controls regarding creative professions. CONCLUSIONS: A familial cosegregation of both schizophrenia and bipolar disorder with creativity is suggested.

Long-term follow-up of transsexual persons undergoing sex reassignment surgery: cohort study in Sweden.

CONTEXT: The treatment for transsexualism is sex reassignment, including hormonal treatment and surgery aimed at making the person's body as congruent with the opposite sex as possible. There is a dearth of long term, follow-up studies after sex reassignment. OBJECTIVE: To estimate mortality, morbidity, and criminal rate after surgical sex reassignment of transsexual persons. DESIGN: A population-based matched cohort study. SETTING: Sweden, 1973-2003. PARTICIPANTS: All 324 sex-reassigned persons (191 male-to-females, 133 female-to-males) in Sweden, 1973-2003. Random population controls (10:1) were matched by birth year and birth sex or reassigned (final) sex, respectively. MAIN OUTCOME MEASURES: Hazard ratios (HR) with 95% confidence intervals (CI) for mortality and psychiatric morbidity were obtained with Cox regression models, which were adjusted for immigrant status and psychiatric morbidity prior to sex reassignment (adjusted HR [aHR]). RESULTS: The overall mortality for sex-reassigned persons was higher during follow-up (aHR 2.8; 95% CI 1.8-4.3) than for controls of the same birth sex, particularly death from suicide (aHR 19.1; 95% CI 5.8-62.9). Sex-reassigned persons also had an increased risk for suicide attempts (aHR 4.9; 95% CI 2.9-8.5) and psychiatric inpatient care (aHR 2.8; 95% CI 2.0-3.9). Comparisons with controls matched on reassigned sex yielded similar results. Female-to-males, but not male-to-females, had a higher risk for criminal convictions than their respective birth sex controls. CONCLUSIONS: Persons with transsexualism, after sex reassignment, have considerably higher risks for mortality, suicidal behaviour, and psychiatric morbidity than the general population. Our findings suggest that sex reassignment, although alleviating gender dysphoria, may not suffice as treatment for transsexualism, and should inspire improved psychiatric and somatic care after sex reassignment for this patient group.

Genome-wide search for QTLs for apolipoprotein A-I level in elderly Swedish DZ twins: evidence of female-specific locus on 15q11-13.

The effect of genetic variants underlying atherosclerosis is thought to be mediated through intermediate phenotypes such as serum cholesterol levels. Localization of quantitative trait loci influencing levels of serum lipids and (apo)lipoproteins may aid in the search for determinants of susceptibility to atherosclerotic diseases. Since apolipoprotein A-I is the primary protein constituent of high-density lipoprotein, it is considered to be critical for the antiatherogenic effect of high-density lipoproteins. We describe here an effort to map loci influencing apolipoprotein A-I levels. Measurements of apolipoprotein A-I levels and genome scans with more than 1000 microsatellite markers were successfully performed in both members of 501 pairs of fraternal twins from Sweden. Variance component linkage analysis was undertaken to map quantitative trait loci. In the total study sample, two loci showed comparable suggestive evidence of linkage, 6p21-12 (LOD=2.4) and 12q23 (LOD=2.4). Sex-limited analyses revealed significant female-specific linkage at marker D15S156 on 15q11-13 (LOD=4.1). The loci on 12q and 15q in the present study confirm previously reported loci for apolipoprotein A-I, while the peak on chromosome 6p lends further support to a locus influencing several phenotypes related to atherosclerosis. Intriguingly, the presence of genes belonging to the phospholipase A2 superfamily under three out of four observed linkage peaks would lend some support to the view that this group of genes might collectively represent candidates as apolipoprotein A-I level regulators.