HARWICK INSTITUTE FOR COGNITIVE RESEARCH BEHAVIORAL GENETICS LABORATORY TWIN COHORT FOLLOW-UP ANALYSIS Document date: May 22, 1998 Prepared by: M.L. Reyes, Ph.D. Classification: INTERNAL — DO NOT DISTRIBUTE ======================================================================= I. OVERVIEW ======================================================================= This document presents follow-up findings for the twin pairs enrolled in the Divergence Phenotype Study cohort. Twin pairs provide the methodologically cleanest test of heritability and genetic versus environmental contribution to the phenotype. The current analysis covers 11 monozygotic (MZ) pairs and 6 dizygotic (DZ) pairs enrolled through 1997. Pairs are designated by the prefix TW- followed by pair number and twin letter (A/B). A = first-assessed twin in pair; B = second. Heritability estimate from twin data: 0.74 (MZ concordance 0.81, DZ concordance 0.43). This is consistent with the parent-offspring regression estimate of 0.71 from the 1993 cohort summary. ======================================================================= II. MZ TWIN PAIR SUMMARY ======================================================================= TW-01A / TW-01B Zygosity: MZ (confirmed via blood typing) Birth year: 1954 Origin: Eugene, OR G1 military service: Yes (paternal grandfather, Army, 1934–1941) Expression (TW-01A): HIGH Expression (TW-01B): HIGH Concordant: Yes Notes: Both enrolled in GPE program, Corvallis, 1966. Cooperative subjects. Both report similar childhood experiences, similar self-described "processing delay." No program documentation located. TW-02A / TW-02B Zygosity: MZ Birth year: 1958 Origin: Redding, CA G1 military service: Yes (maternal grandfather, Army, 1932–1938) Expression (TW-02A): HIGH Expression (TW-02B): MODERATE Concordant: Partial Notes: TW-02B sustained a significant head injury at age 11. PI notes that post-injury behavioral changes may complicate DPB scoring for TW-02B. Treating this pair as partial concordance pending review. TW-02A enrolled in GPE program; TW-02B was not (injury occurred prior to enrollment window). TW-03A / TW-03B Zygosity: MZ Birth year: 1961 Origin: Arlington, VA G1 military service: Yes (paternal grandfather, Army, 1929–1940) Expression (TW-03A): HIGH Expression (TW-03B): HIGH Concordant: Yes Notes: Both enrolled in what family describes as a residential enrichment program, 1972, location described as "Virginia, somewhere outside the city." Neither twin can provide more specific location. Neither has documentation. Program not located in public records. TW-03B declined to continue participation after first assessment. TW-03A remains in study. TW-04A / TW-04B Zygosity: MZ Birth year: 1963 Origin: Pueblo, CO G1 military service: Yes (paternal grandfather, Army, 1931–1937. Stationed at Fort Garland, 1933–1935, per partial service record.) Expression (TW-04A): HIGH Expression (TW-04B): HIGH Concordant: Yes Notes: Both declined further participation in 1995. No explanation given. PI attempted follow-up contact; no response. TW-05A / TW-05B Zygosity: MZ Birth year: 1956 Origin: Salem, OR G1 military service: Records unavailable. Expression (TW-05A): MODERATE Expression (TW-05B): MODERATE Concordant: Yes Notes: Neither enrolled in specialized program. Standard gifted program (school district records confirmed). Less pronounced profile than the majority of skip-generation families. PI notes as possible partial or attenuated expression variant. TW-06A / TW-06B Zygosity: MZ Birth year: 1960 Origin: Stockton, CA G1 military service: Yes (maternal grandfather, Army, 1930–1942) Expression (TW-06A): HIGH Expression (TW-06B): HIGH Concordant: Yes Notes: TW-06A enrolled in GPE program, Sacramento, 1971. TW-06B was not assessed for program enrollment per family account ("they only wanted one of us"). Both subjects found this detail notable. PI also notes this detail. TW-07A / TW-07B Zygosity: MZ Birth year: 1965 Origin: Richmond, VA G1 military service: Yes (paternal grandfather, Army, 1935–1943) Expression (TW-07A): HIGH Expression (TW-07B): MODERATE Concordant: Partial Notes: Discordance in MZ pair without obvious environmental explanation (no significant medical history, both raised in same household through age 18). Partial concordance flagged for review. PI considers this the second most anomalous pair in the dataset. See also TW-11 (below). TW-08A / TW-08B Zygosity: MZ Birth year: 1959 Origin: Medford, OR G1 military service: Not confirmed. Expression (TW-08A): LOW Expression (TW-08B): LOW Concordant: Yes (low) Notes: G1 data incomplete. This family does not fit the primary demographic cluster. Retained in cohort as a comparison case. Expression consistent with general-population baseline. TW-09A / TW-09B Zygosity: MZ Birth year: 1962 Origin: Colorado Springs, CO G1 military service: Yes (maternal grandfather, Army, records partial) Expression (TW-09A): HIGH Expression (TW-09B): HIGH Concordant: Yes Notes: Both enrolled in GPE program, Colorado Springs, 1972. Both report nearly identical memories of the program. PI notes this is consistent with MZ pairs but also with shared confabulation in the absence of documentation. Unable to verify program details through public records. TW-10A / TW-10B Zygosity: MZ Birth year: 1957 Origin: San Jose, CA G1 military service: Yes (paternal grandfather, Army, 1930–1939) Expression (TW-10A): HIGH Expression (TW-10B): HIGH Concordant: Yes Notes: Both declined initial participation. TW-10A subsequently contacted PI independently (1991) and has been cooperative. TW-10B remains declined. TW-10A has provided family history data for G1 and G2 from memory. No documentary confirmation available. TW-11A / TW-11B Zygosity: MZ (confirmed, high confidence) Birth year: 1964 Origin: Portland, OR G1 military service: Yes (paternal grandfather, Army, 1931–1938. Stationed at Fort Garland, 1932–1936. Service records: PARTIAL RELEASE, see foia_response_94b.pdf for related documentation.) Expression (TW-11A): LOW Expression (TW-11B): HIGH Concordant: NO --- NOTE FROM PI (added 04 December 1997) --- TW-11A and TW-11B are confirmed MZ twins. Zygosity testing was conducted by an independent laboratory (Oregon Health Sciences University, April 1994) at the PI's request following initial assessment results. The result is not in doubt. TW-11B has a high-expression divergence phenotype profile — the strongest in the current cohort, by DPB scoring. TW-11A has a profile consistent with the general-population low-expression baseline. They are genetically identical. The PI has reviewed the environmental history of both subjects in detail. They were raised in the same household. They attended the same schools through age 16. There is no significant medical divergence. The relevant difference in their histories is this: In 1973, TW-11B was enrolled in a specialized assessment program run through the Portland school district. TW-11A was not enrolled. The program ran for approximately eight months, after which TW-11B was, in the family's account, "returned" to regular schooling with no explanation given. TW-11A has no memory of this period as unusual. TW-11B has described the experience in terms the PI finds consistent with other GPE program participant accounts. The PI does not have a Mendelian model that accounts for this discordance. Identical twins should not show this divergence in a trait with a heritability of 0.74. There are two possible interpretations. First: the heritability estimate is wrong and the trait is substantially more environmentally mediated than the twin data otherwise suggests. This would require explanation for the strong parent-offspring correlations. Second: something that happened to TW-11B during or after the 1973 program produced an epigenetic modification that is expressed as the divergence phenotype — meaning the phenotype we have been treating as genetic inheritance is, at least in part, induced. The PI does not know which interpretation is correct. She is not sure those are the only two interpretations available. She notes that she is not going to set this document down and walk away from it. --- End PI note --- ======================================================================= III. DZ TWIN PAIR SUMMARY (ABBREVIATED) ======================================================================= DZ pairs show concordance consistent with first-degree relative rates (approximately 0.43), supporting the heritability estimate. No DZ pair anomalies comparable to TW-11 were observed. Pairs: TW-DZ-01 through TW-DZ-06 All DZ concordance data is consistent with expected heritability parameters. Full DZ data available on request. ======================================================================= IV. SUMMARY OBSERVATIONS ======================================================================= The twin data generally supports a substantial genetic contribution to the divergence phenotype. The heritability estimate of 0.74 is robust across multiple calculation methods. The TW-11 pair constitutes a significant anomaly that the PI does not currently have a theoretical framework to accommodate. It is the most important data point in the current dataset. It may also be the most important data point the PI has encountered in this research. If the divergence phenotype can be induced — if it is not solely inherited but can be produced in a genetically susceptible individual through external intervention — then the implications extend well beyond the scope of this study. The PI will continue following this question. ======================================================================= Document end. MLR — 22 May 1998