1

Genes and Environment: Is it Nature or Nurture?

Kenneth F. Schaffner, M.D., Ph.D.University Professor of Medical Humanities

Professor of Philosophy     George Washington University

medhum@gwu.edu

            

2

Qualifying the subtitle

• It’s actually “nature AND nurture” and means all of the below:– Gene effects

– Environment effects

– Genes AND environment effects (where genes and environments can work together or work against each other and possibly in non-linear ways)

3

Why are we concerned about genes and/or environment?

• Suppose a test for a deleterious gene is positive but environment does not allow a gene effect to manifest itself or “penetrate” (e.g., breast cancer [BRCA1])—good!

• Suppose a test for a deleterious gene is positive and environment facilitates the gene to manifest itself (e.g., Alzheimer’s Disease [APOE4 and head trauma])– bad!

• Also, the “nature or nurture” issue is especially controversial in behavioral genetics

4

Special concerns in behavioral genetics area, for example:

• IQ (The Bell Curve of 1994) – is IQ “heritable”?

• Sexual orientation – is there a “gay gene”?• Genes and aggression/crime—UMD

conference• Likelihood of bad eugenics implications:

sterilization programs for the “feebleminded,” and the Holocaust

5

Behavioral genetics will not be covered today, because:

• No genes have been specifically identified for behavioral traits that have been well-enough replicated or have reasonably broad application [though “novelty-seeking” (associated with DRD4) is almost there]. Thus they are NOT being tested for.

• Many genes for psychiatric disorders have been identified, but they have not been replicated well-enough, and are NOT used diagnostically.– For example, in schizophrenia there are reports of linked regions

on chromosomes 1q, 4p, 4q, 6p, 6q, 8p, 9q, 12 p, 13q, 18p, 18q, 20p, 21q, 22q and Xp, but only 1q21-22 has a lod score that is highly significant (6.5). However that study is only in 22 extended families.

6

Behavioral and psychiatric genetics

• Detailed summaries with references to the behavioral and psychiatric literature are available from me at:

• medhum@gwu.edu• This research has been supported by the Science and

Technology Studies Program at the National Science Foundation, but any opinions, findings, and conclusions or recommendations expressed in this talk are mine and do not necessarily reflect the views of the National Science Foundation.

7

Identified genes and the environment

• Though there has been major progress made in identifying single gene rare disorders that are typically highly penetrant (e.g., cystic fibrosis, Huntington’s disease) – These may be the “low hanging fruit” (Risch, 2000),

• Progress in identifying genes contributing to common diseases (late onset Alzheimer’s Disease [LOAD], non-BRCA1/2 breast cancer, Type 1 or type 2 diabetes, heart disease) has been slower

8

Examples for today’s discussion about nature and nurture

• Common diseases: Breast, prostate, and colorectal cancers

• Important but fairly rare forms of disease: BRCA1/2 related breast cancer (~5% of breast CA)

• Fairly common disease: Late onset Alzheimer’s Disease (LOAD) (4M in USA at present and numbers expected to rise)

9

Why use these examples?

• The common cancers, breast (12 % of women in a lifetime), prostate (16 % of men in a lifetime) have recently been reported on regarding the genetic and environmental contributions using a classical method of twin studies – quantitative genetics

• The fairly rare BRCA1/2 example has served to identify a molecular genetics approach to an important disease that has related, but so far no closely-tied, environmental factors

• Late onset Alzheimer’s Disease studies are identifying gene-gene and gene environment interactions in a specific way.

10

Genes and Environments in Cancer

“Decades long work has resulted in the widely accepted estimate that 80 to 90 percent of human cancer is due to environmental factors.…

The gold standard for distinguishing genetic from environmental traits has been the study of twins.”

(Robert N. Hoover, M.D., National Cancer Institute NEJM-2000)

11

12

This study uses quantitative genetics (as contrasted with molecular

genetics)

• Genetic and environmental contributions to cancers at 28 anatomical sites were studied in a sample of almost 45,000 pairs of twins from the Swedish, Danish, and Finnish twin registries, some cohorts going back to the 19th century

13

Swedish, Danish, and Finnish study

• At least one cancer occurred in ~11,000 persons among 9500 pairs of twins

• Increased genetic risk was shown for stomach, colorectal, lung, breast, prostate cancers

• Statistical modeling was used for 11 kinds of cancer to estimate genetic versus environmental contributions

• Three kinds of cancers were statistically significant genetically (in this study)

14

Some Scandinavian results

• Prostate cancer = 42% of risk explained by heredity (range 29-50 for 95% confidence band)

• Colorectal cancers = 35% due to heredity (range 10-48%) • Breast cancer = 27% due to heredity (range 4-41%)• The implication drawn is that more than half the risk of

cancer is due to the environment.• Virtually all is due to “unshared” environment rather

than common environments (e.g. family diet, in home smoke exposure)

• For cancer at the common sites in identical twins, the rate of concordance is generally less than 15 percent.

15

Some Scandinavian limitations from Hoover’s comments and NEJM follow-up letters-1

• This is a general level study using anonymous genetic and environmental factors

• Exposures to potential carcinogens were not examined, so interactions between genes and environments could not be studied

• These interactions are explicitly not assumed by the analyzing model

16

Some Scandinavian limitations from Hoover and NEJM follow-up letters-2

• The “unshared” environment component may well contain random (somatic) mutation effects rather than true environmental effects (but mutation effects may be a surrogate for them)

• Different sets of factors may be operating in different sets of twins

• Twin studies like this one only attribute a lower limit to genetic factors, and specific environmental attribution is not possible (Peto comment)

17

Promising Scandinavian results and implications -- Hoover

• The fatalism of the general public about the inevitability of genetic effects should be easily dispelled (low identical twin concordance rate ~15%)

• Information about types of environmental exposure that affect the risk of cancer should point to genes that might modify this risk, and the identification of genes associated with risk could help to indicate previously unrecognized environmental risk factors.

• Perhaps it is time to drop the competition implied by talking

about a debate over nature versus nurture in favor of efforts to exploit every opportunity to identify and manipulate both

environmental and genetic risk factors to improve the control

of cancer.

18

Scandinavian results and implications—Bottom line

• The study has its limitations but is consistent with other results indicating a major environmental role in carcinogenesis. It’s not just the genes.

19

How to study Genes and Environments better?

• Consider some of the BRCA1/2 studies that are molecular

• The APOE Alzheimer Disease studies, also molecular

• New promise from SNPs for studying genes and environments?

20

BRCA1 (breast cancer gene number 1)

• This autosomal dominant and highly penetrant gene has been the focus of many studies and discussions about testing

• It only accounts for about ~5% of breast cancer, so it is fairly rare

• The lifetime risk varies from 85% in high risk families to ~50% in a community study involving Ashkenazi Jewish women

21

BRCA1– lifetime risks-high risk family- Ponder, 1997

22

BRCA1– lifetime risks-AJ-community study- Struewing et al, 1997

23

BRCA1– testing advice and environmental influences

• Whether to be tested for BRCA1/2 is a very complex decision. An excellent discussion of the pros and cons in the case of a “Mrs. T” can be found in Garber and other’s in JAMA, 1999

• Environmental factors and probably other genes most likely influence the risk

• Many research studies are investigating these factors, but no definitive list is yet available

• Examples: studies of BRCA1 deficient cells show radiation sensitivity (including UV radiation)

24

Breast cancer

• Many other genes for breast cancer are currently being investigated

• Results so far show that breast cancer is very diverse (heterogeneous)

• And that there are complex environmental interactions

• The molecular approach will not provide quick or simple answers in cancer genetics

25

NCI will prioritize gene-environmental studies in 2002

26

The Alzheimer Disease Story: An excellent example to study G-E

• Alzheimer's Disease (AD) provides us both with a classical Mendelian etiological picture as well as with complex trait patterns

• There are three Mendelian forms of early-onset AD, due to dominant mutations in genes APP, PS1 and PS 2 but these are rare: < 1% of AD cases

• The strongly replicated APOE4 locus on chromosome 19 associated with late onset form Alzheimer's Disease (LOAD), in contrast, is a susceptibility gene, neither necessary nor sufficient for the disease. It is a risk factor. Testing is not recommended except in special circumstances, such as research.

27

The Alzheimer Disease Story

• The APOE4 and APOE2 and 3 alleleic forms also interact with other genes and with the environment. APOE alleles 2 and 3, appear to protect individuals with the APP mutation.

• Environmental head trauma, studied in former football players by Kutner et al., 2000, appears to interact with APOE4 to produce a worse prognosis.

• Other susceptibility genes for late onset AD continue to be investigated. Allen Roses group earlier identified a possible locus on chromosome 12 and recently reported one on chromosome 9.

28

The Alzheimer Disease Story

• This disease in its LOAD form is likely to be heterogeneous, with a final common pathological pathway

• Environmental risk factors and preventive factors are being studied

• These will probably interact with the genetic component of LOAD in complex ways

29

New promise from SNPs for studying genes and environments?

• SNPs are single nucleotide polymorphisms that may be able to single-out individualized genetic susceptibilities

• They are also seen as providing a means to individualize drug treatments to avoid side effects and provide effective remedies

30

SNPs for studying genes and environments

• Allen Roses, the discoverer of the APOE LOAD gene, suggests that adverse event pharmacogenetics, in which someone has a bad but very rare reaction to a drug, is a prototype for understanding gene-environment interaction

31

AE-Pharmacogenetics combines identifiable environmental factors and

genetic susceptibilities• An environmental toxin or poison, [or] a chemical

that we call a medicine, is administered to a patient who is genetically susceptible. The patient develops a phenotypic reaction similar to other people in the population who share an uncommon set of genetic variables spread over the genome. [my emphasis]

• From Roses, 2001, in press

32

SNPs for studying genes and environments

• Roses also cautions us not to confuse AE-pharmacogenetics testing with genetic testing for highly penetrant mutations or for susceptibility genes. Pharmacogenetics testing may be done so that those tested are not screened for genetic disease(s).

33

From Roses, 2000

34

Science Policy Implications of the Nature-Nurture Issue(s)-1

• Science: Though this is a genomics era, most diseases have important environmental components. The nature or nurture debate concludes with a nature and nurture answer.

• Policy: Coupled gene-environmental studies may be much more revealing of disease causes and the basis for more effective preventative strategies.

35

Science Policy Implications of the Nature-Nurture Issue(s)-2

• Science: Extraordinary progress in gene mapping is yet to be mirrored by understanding of how the genes work in diverse individuals and environments.

• Policy: Testing and research need to proceed, but those tested need to be well informed to protect them against misunderstandings fueled by a gene-focused view. Similar potential misunderstandings argue for protections in health insurance and the workplace, certainly now, and arguably for the future.