Supplementary information for Methods and materials

Sample collection and evaluation

We recruit 140 families using nation-wide registers to identify all individuals born between 1940 and 1969 who were hospitalized for BPD-I between 1969 and 1991. Before 1987 diagnoses were made using the International Classification of Diseases, version 8 (ICD-8) (1). From 1987 onwards diagnoses were coded according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, revised third edition (DSM-III-R) (2). Information on first-degree relatives was gathered from the National Population Register.

Eight additional families were identified from among a schizophrenia family sample, which had been collected using the same registers (3). These families were included because the diagnostic evaluation revealed family members with schizoaffective bipolar type disorder. The remaining individuals in our sample consisted of BPD twin samples from 32 families. We used the Finnish twin cohorts to identify twins in which at least one of the twins was affected with BPD (4). Ascertainment strategy and sample collection are described elsewhere in more detailed (3-5).

For all families studied here, the other family members were either unaffected or diagnosed with other mental disorders, including depression, alcohol-related disorders, and delusional, adjustment, dysthymic or panic disorder. The diagnoses were based on SCID interviews or all available information gathered from hospital records.

Given the focus of the present study, two alternative diagnostic groups were applied. The first diagnostic group covered bipolar spectrum disorders: BPD-I, BPD-II, BPD-not-otherwise-specified (NOS) and cyclothymia. The second group included only individuals with the presence of life-time psychotic symptoms. This group included patients with the diagnoses of BPD-I (with intermittent psychotic features), schizoaffective disorder (SA), psychotic depression, schizophrenia, and psychosis NOS. There was an overlap of 162 individuals between the two groups.

Neuropsychological tests

Neuropsychological test data was available for 134 individuals in Phase I of the study and for 25 additional individuals in Phase II of the study, thus altogether for 159 individuals from 65 families (6, 7). The Vocabulary, Similarities, Digit Symbol and Block Design subtests from the Finnish version of the Wechsler Adult Intelligence Scale – Revised (WAIS-R) (8) were included to assess general ability, verbal abstraction, psychomotor speed and visuospatial ability, respectively. From the Wechsler Memory Scale-Revised (WMS-R) (9), we included the Digit Span and Visual Span forward and backward subtests to assess auditory attention and working memory, and visual attention and working memory, respectively, and the Logical Memory and Visual Reproduction subtests to assess verbal and visual memory, respectively, in both immediate and delayed conditions. The California Verbal Learning Test (CVLT) was included to assess learning in free short and long delay recall trials, recognition memory and long-delay retention (10). The interference score from the Stroop Color and Word Test (11) was included as a measure of selective attention and executive functioning, and the Controlled Oral Word Association Test (COWAT) to assess phonemic and semantic verbal fluency (12).

References:

1. WHO. (1967) Manual of the international statistical classification of diseases, injuries and causes of death, 8th ed. 8th ed. Geneva: Word Health Organization.

2. American Psychiatric Association. (1994) Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). 4th ed. Washington D.C.: American Psychiatric Association.

3. Hovatta I, Varilo T, Suvisaari J, Terwilliger JD, Ollikainen V, Arajarvi R, et al. (1999): A genomewide screen for schizophrenia genes in an isolated Finnish subpopulation, suggesting multiple susceptibility loci. Am J Hum Genet 65:1114-24.

4. Kieseppa T, Partonen T, Haukka J, Kaprio J, Lonnqvist J (2004): High concordance of bipolar I disorder in a nationwide sample of twins. Am J Psychiatry 161:1814-21.

5. Ekholm JM, Pekkarinen P, Pajukanta P, Kieseppa T, Partonen T, Paunio T, et al. (2002): Bipolar disorder susceptibility region on Xq24-q27.1 in Finnish families. Mol Psychiatry 7:453-9.

6. Kieseppa T, Tuulio-Henriksson A, Haukka J, Van Erp T, Glahn D, Cannon TD, et al. (2005): Memory and verbal learning functions in twins with bipolar-I disorder, and the role of information-processing speed. Psychol Med 35:205-15.

7. Antila M, Tuulio-Henriksson A, Kieseppa T, Eerola M, Partonen T, Lonnqvist J (2007): Cognitive functioning in patients with familial bipolar I disorder and their unaffected relatives. Psychol Med 37:679-87.

8. Wechsler D. (1981) Adult Intelligence Scale-Revised (WAIS-R), Manual. Corporation TP, editor. Cleaveland, OH: Harcourt Brace Jovanovich, Inc.

9. Wechsler D. (1987) Wechsler Memory Scale-Revised (WMS-R), Manual. Corporation TP, editor. San Antonia, Tx: Harcourt Brace Jovanovich, Inc.

10. Delis DKJ, Kaplan E, Ober BA. (1987) California Verbal Learning Test. Manual. Recearch Edition. San Antonia, TX: The Psychological Corporation Harcourt Brace and Company.

11. Golden C. (1978) Stroop Color and Word Test. Chicago: Stoelting.

12. Benton A, Hamster, K. (1989) Multilingual Aphasia Examination Manual. Iowa City: University of Iowa.