OT: Big surprise-- No gene for schizophrenia

[Guest guest]

Note on the article: Franz Kallmann was a eugenicist and collaborator

prior to leaving nazi Germany. He called for the forced sterilization

of not only schizophrenics but their entire families.

From: " VERACARE " <veracare@...>

" Infomail1ahrp (DOT) org " <Infomail1@...>

Subject: Schizophrenia Genes: Are We Really Coming Up Blank?

Date: Fri, 4 Apr 2008 14:01:42 -0400

ALLIANCE FOR HUMAN RESEARCH PROTECTION

Promoting Openness, Full Disclosure, and Accountability

http://www.ahrp.org and http://ahrp.blogspot.com

FYI

In the 1930s eugenicists proclaimed mental disorders were " proven " to

have a genetic basis. Psychiatrist Franz J. Kallmann, an influential

geneticist of the period said that the aim of his 1938 schizophrenia

family study was " to offer conclusive proof of the inheritance of

schizophrenia. " [1 See, note]

A major report by Dr. Alan and 22 colleagues in the official

journal of the American Psychiatric Society, acknowledges that the

science isn't there to support the claim of a genetic cause for

schizophrenia. Their comprehensive analysis casts doubt on the

genetic hypothesis for schizophrenia:

" our findings suggest it is unlikely that true associations exist at

the population level for the alleles that have formed the basis for

the large candidate gene literature for these 14 postulated

schizophrenia candidate genes. " [2]

The sample included 1,870 cases (schizophrenia and schizoaffective

disorder)

and 2,002 screened comparison subjects (i.e. controls), all of

European

ancestry, with ancestral outliers excluded based on analysis of

ancestry-informative markers.

" Neither experiment-wide nor gene-wide statistical significance was

observed

in the primary single-SNP analyses or in secondary analyses of

haplotypes or

of imputed genotypes for additional common HapMap SNPs. Results in

SNPs

previously reported as associated with schizophrenia were consistent

with

chance expectation, and four functional polymorphisms...did not

produce

nominally significant evidence to support previous evidence for

association. "

Psychiatry has so far failed to provide a valid explanation for any

biological underlying cause for mental disorders. After decades of

research

utilizing sophisticated technology, no genetic, biochemical, or other

biological locus for psychiatric disorders has been found.

The " chemical

imbalance " theory has been debunked as a " metaphor, " Thus, the

presumed

biological basis underlying psychiatric diagnoses remains unvalidated.

http://medicine.plosjournals.org/perlserv/?request=get-

document & doi=10.1371/

journal.pmed.0020392

Psychologist, Jay ph, has written books and numerous journal

articles

critical of genetic research in psychiatry.

http://www.jayjoseph.net/Publications.html

He provides a cogent critique of psychiatry's underlying assumptions

and

flawed methodology. He believes that molecular genetic research in

psychiatry has failed to find specific genes that cause psychiatric

disorders because such genes are unlikely to exist. [3]

In light of the failure to pinpoint any biological basis for mental

disorders, Psychiatry will be hard pressed to justify its continued

prescribing of highly toxic drugs whose severe adverse effects are

measurable and documented in chronic disability and early deaths.

Psychiatry's aggressive prescribing practices—including prescribing

untested

multi-drug combinations " cocktails " even for young children—lack a

medico-scientific basis.

Psychiatry's prescribing of antipsychotics singly and in drug

cocktails is

akin to using a chemical sledgehammer. Lacking a science-based

biological

target, such a shotgun approach is carried out in complete ignorance.

Four-year old, Riley was a casualty of psychiatrists'

irresponsible

use of toxic drugs for a dubious biological diagnosis at age 28

months.

References:

1. Dr. Kallmann trained under Dr. Ernst Rüdin, one of the architects

of

racial hygiene policies in Nazi Germany, fled to the US in 1933.

Kallmann F: The Genetics of Schizophrenia: A Study of Heredity and

Reproduction in the Families of 1,087 Schizophrenics. New York, J. J.

Augustin, 1938

2. Alan R. , M.D. + 22 colleagues. No Significant Association

of 14

Candidate Genes With Schizophrenia in a Large European Ancestry

Sample:

Implications for Psychiatric Genetics, Am J Psychiatry 2008; 165:497–

506.

3. Jay ph's latest book, The Missing Gene: Psychiatry, Heredity,

and the

Fruitless Search for Genes, 2006, New York: Algora.

104>

Contact: Vera Hassner Sharav

veracare@...

212-595-8974

http://ajp.psychiatryonline.org/cgi/content/full/165/4/420#top

American Journal of Psychiatry

Editorial

Schizophrenia Candidate Genes: Are We Really Coming Up Blank?

P. Hamilton, M.D., Ph.D.

The most comprehensive genetic association study of genes previously

reported to contribute to the susceptibility to schizophrenia by

Gejman et

al. is published in this issue of the Journal. The study by

et al.

(1)

set out to examine whether polymorphic DNA sites, or single nucleotide

polymorphisms (SNPs), in 14 candidate genes previously argued by the

authors

and other researchers to be associated with schizophrenia would

continue to

do so in a large sample of European ancestry. The authors analyzed

433 SNPs

in these genes in the hope of representing, or " tagging, " the known

common

DNA variation in those genes. They also examined an additional 215

SNPs in

these genes used in the earlier published studies or that occur in

functionally relevant regions of the genes. Before discussing their

results,

it may be helpful to set the stage for this article.

It is often not appreciated that the last decade of genetic studies

in schizophrenia has generated findings suggesting that a number of

genes

are associated with schizophrenia across multiple studies (2)

..

Not all studies of any particular gene are positive, and the

contribution

toward risk that any individual gene makes appears to be small. Many

are

also surprised that some of these genes were initially found using

positional cloning, the systematic identification and localization of

genes

using linkage analysis in families segregating schizophrenia.

Examples of

such genes include dystrobrevin-binding protein 1 (DTNBP1),

neuregulin 1

(NRG1), and D-amino acid oxidase activator (DAOA). Similarly, positive

studies have emerged for genes pursued after being found at sites of

chromosomal abnormalities. Disrupted in schizophrenia 1 (DISC1) was

identified at the site of a chromosomal translocation segregating with

schizophrenia (and other mental disorders) in a single pedigree.

Likewise,

the catechol-O-methyltransferase (COMT) gene occurs in a large common

deletion of a segment of chromosome 22 that by itself increases the

risk of

schizophrenia by greater than 20-fold. et al. (1)

these genes as well as those connected to animal models (PP3CC, also

residing in a reported linkage region) or pharmacological hypotheses

(HTR2A,

DRD2) in their analyses. This study stands above others because the

authors

attempt to bring to bear two critical factors on their experiment—a

large

sample and comprehensive genotyping.

Given that many of the studies suggesting that these 14 genes are

associated with schizophrenia were of modest size, the authors'

sample of

nearly 1,900 cases and 2,000 comparison subjects provides, at least in

theory, substantial statistical power for confirming the results of

the

earlier studies. The authors were able to cobble together 1,952

persons

recruited from multiple sources and diagnosed with schizophrenia or

schizoaffective disorder, collected over 15 years from 12 sites in 10

U.S.

states, plus a single site in Australia, which also contributed the

most

subjects. About 17% of the individuals were derived from pedigrees

with

multiple members with schizophrenia. The authors also collected a

comparison

group composed of adults who completed a short online self-report

clinical

assessment. Although these screened comparison subjects may be

preferable to

random uncharacterized individuals, given the high prevalence of

psychiatric

disorders, there may be hidden biases influencing who elected to

participate

in a comparison group.

With these strengths—reasonable candidate genes, a large, rigorously

phenotyped sample, and a dense set of SNPs—what do the authors find?

They

find that none of the polymorphisms were associated with the

schizophrenia

phenotype at a reasonable threshold for statistical significance.

Removal of

schizoaffective disorder cases did not alter the results, nor did

careful

correction for subtle ancestry differences between cases and

comparison

subjects. Haplotypes composed of multiple markers were not

associated, and

neither were imputed genotypes of SNPs not directly examined in the

study.

Of the 69 SNPs that had shown positive association to these genes in

previous studies, only four—in TAAR6, HTR2A, and RGS4—showed even

nominal

association in et al. (1)

..

The distribution of test statistics suggests nothing outside of what

would

be expected by chance.

What might explain these negative findings? The simplest explanation

is that for the broadly recruited cases and comparison subjects used

in this

study, common DNA variation in these genes is just not correlated

with the

schizophrenia phenotype, as defined by the investigators. This does

not

necessarily mean we should dismiss the findings of the previous

studies,

where those results may in fact be valid for specific samples. For

example,

the authors previously reported positive associations to DTNBP1 and

TAAR6 in

a subset of the same families that contributed to the sample used in

the

current article (3

,

4)

..

The discrepancy between that earlier positive finding and the current

negative one is not addressed in et al. (1)

but may highlight the relative merits of family-based studies versus

methods

using unrelated cases and comparison subjects. Unless we believe that

the

current results completely negate the previous findings, the

difference in

results may argue for stronger confidence in family-based analyses.

Although

the authors have cast a negative interpretation of their findings, a

simple

thought experiment underscores the problem of accommodating

corrections for

multiple testing while simultaneously examining several hypotheses

backed by

prior evidence. If the authors had genotyped only the single SNP in

the STX7

gene that provided their strongest result instead of all 648 SNPs,

would the

interpretation of the data have fared differently despite arriving at

the

same statistic?

Additionally, the large study of et al. (1)

may not have had the required power to detect genetic effects of small

magnitude. Although the authors report that they should be able to

detect

genotypic relative risks (the risk of being affected for an

individual with

a single susceptibility allele compared to an individual with no

susceptibility alleles) as low as 1.25, even this may be insufficient

for

reliably observing weak associations.

Using recent genome-side association studies of type 2 diabetes as a

way to

illustrate this problem, not a single study among three large samples,

together comprising 32,000 subjects, was able to conclusively show

the HHEX

gene as a type 2 diabetes risk locus. Combining data from the three

independent samples showed the same small odds ratio (1.13) seen in

the

individual studies but with more persuasive statistical significance

(p=5.70x10–10) (5)

,

implying that tens of thousands of samples may be required to detect

small

but real genetic effects. This same problem had been faced years

earlier in

type 2 diabetes research, with a strong candidate gene called PPARG,

now

well established as a type 2 diabetes susceptibility gene and the

target for

thiazolidinediones, such as rosiglitazone. In one large study, nominal

statistical significance was reached for only one of four independent

samples, yet when data from all four groups were combined, a stronger

association emerged (6)

..

Another explanation involves the type of DNA variation tested in this

study.

It is plausible that instead of common SNPs distributed widely across

populations, schizophrenia may be influenced by numerous rare but

deleterious mutations or by large-scale variation in chromosome

structure,

models increasingly observed in other disorders, such as autism (7

,

8)

..

It may also be that the phenotypic definition of schizophrenia in

common use

is not entirely reflective of the underlying genetic architecture,

perhaps

requiring alternative classification schemes taking into account

clinical

features shared between disorders (9)

..

It is also possible that the majority of the samples in the authors'

study

had a less heritable form of the disorder; only 17% of the subjects

were

from pedigrees segregating schizophrenia (i.e., 100% had a positive

family

history), while less than 5% of the remaining large fraction of the

participants reported a family history of disease. Sporadic and

familial

forms of schizophrenia may share common genetic features, but there

is some

indication that de novo mutation may play a prominent role in sporadic

schizophrenia (10)

,

which would render standard linkage disequilibrium gene mapping

approaches

less useful, if not futile.

The most worrisome explanation for the lackluster results may derive

from genetic heterogeneity intrinsic to such studies, despite the

great care

the authors exerted in the design and execution of this work. This

heterogeneity may be due to stochastic factors, local environmental

interactions, or ascertainment biases that may apply differentially

across

sites. For example, it is possible that cases at any one site may be

more

related to one another than they are to comparison subjects or to

cases

collected at other sites. Thus, some fraction of a single subsample

may be

potentially seen as a loose but extended pedigree segregating a

limited

number of risk alleles not seen in other cases. This situation

becomes more

complex if one contemplates the role of combinations or interactions

between

risk variants (11)

..

This could lead to a situation in which a robust finding in one

segment of

the overall sample is washed out by mixing multiple samples from

across the

country or, in the case of et al. (1)

,

from across hemispheres. A direct test of this intra-Caucasian

heterogeneity

would involve stratification of analysis by site.

The fact that the odds ratios seen in this study are in the range of

positive results seen in other complex disorders suggests to some

that even

larger samples might further pin down these results, spurring great

hope

that meta-analysis of multiple samples will provide greater clarity.

It will

be exciting to see how the authors' ongoing genome-wide study (12)

using these samples will fare. The great hope for this strategy is the

identification of novel risk genes for schizophrenia.

The main lesson of this article is that the 14 genes studied may

play little role in schizophrenia in a large and heterogeneous sample

of

European ancestry. But this does not mean that these genes may not

contribute to schizophrenia in specific subgroups, nor does it

suggest that

these genes are not influencing schizophrenia in non-European

samples. Much

work, at both the population and molecular levels, remains before

dismissing

these genes and their connection to schizophrenia.

Address correspondence and reprint requests to Dr. Hamilton,

Department of

Psychiatry and Institute for Human Genetics, University of

California, San

Francisco, 401 Parnassus Ave., Box NGL, San Francisco, CA 94143-0984;

steveh@... (e-mail). Editorial accepted for publication

February

2008

The author reports no competing interests.

REFERCES:

1. AR, Duan J, Levinson DF, Shi J, He D, Hou C, Burrell GJ,

Rice JP, Nertney DA, Olincy A, Rozic P, Vinogradov S, Buccola NG,

Mowry BJ,

Freedman R, Amin F, Black DW, Silverman JM, Byerley WF, Crowe RR,

Cloninger

CR, ez M, Gejman PV: No significant association of 14 candidate

genes

with schizophrenia in a large European ancestry sample: implications

for

psychiatric genetics. Am J Psychiatry 2008; 165:497–506[Abstract/Free

Full

Text]

sid=165/4/497>

2. Owen MJ, Craddock N, O'Donovan MC: Schizophrenia: genes at last?

Trends in Genetics 2005; 21:518–525[CrossRef]

005.06.011 & link_type=DOI> [Medline]

ype=MED>

3. Duan J, ez M, AR, Hou C, Saitou N, Kitano T, Mowry

BJ, Crowe RR, Silverman JM, Levinson DF, Gejman PV: Polymorphisms in

the

trace amine receptor 4 (TRAR4) gene on chromosome 6q23.2 are

associated with

susceptibility to schizophrenia. Am J Hum Genet 2004; 75:624–638

[CrossRef]

link_type=DOI> [Medline]

ype=MED>

4. Duan J, ez M, AR, Hou C, Burrell GJ, Krasner AJ,

Schwartz DB, Gejman PV: DTNPBL (dystrobrevin binding protein 1) and

schizophrenia: association evidence in the 3' end of the gene. Hum

Hered

2007; 64:97–106[CrossRef]

61 & link_type=DOI> [Medline]

ype=MED>

5. Diabetes Genetics Initiative of Broad Institute of Harvard and

MIT, Lund University and Novartis Institutes for BioMedical Research,

Saxena

R, Voight BF, Lyssenko V, Burtt NP, de Bakker PIW, Chen H, Roix JJ,

Kathiresan S, Hirschhorn JN, Daly MJ, TE, Groop L, Altshuler D,

Almgren P, Florez JC, Meyer J, Ardlie K, Bengtsson K, Isomaa B,

Lettre G,

Lindblad U, Lyon HN, Melander O, Newton-Cheh C, Nilsson P, Orho-

Melander M,

Rastam L, Speliotes EK, Taskinen MR, Tuomi T, Guiducci C, Berglund A,

Carlson J, Gianniny L, Hackett R, Hall L, Holmkvist J, Laurila E,

Sjogren M,

Sterner M, Surti A, Svensson M, Svensson M, Tewhey R, Blumenstiel B,

Parkin

M, DeFelice M, Barry R, Brodeur W, Camarata J, Chia N, Fava M,

Gibbons J,

Handsaker B, Healy C, Nguyen K, Gates C, Sougnez C, Gage D, Nizzari M,

SB, Chirn GW, Ma Q, Parikh H, D, Ricke D, Purcell

S:

Genome-wide association analysis identifies loci for type 2 diabetes

and

triglyceride levels. Science 2007; 316:1331–1336[Abstract/Free Full

Text]

sid=316/5829/1331>

6. Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC,

Nemesh J, Lane CR, Schaffner SF, Bolk S, Brewer C, Tuomi T, Gaudet D,

Hudson

TJ, Daly M, Groop L, Lander ES: The common PPARgamma Pro12Ala

polymorphism

is associated with decreased risk of type 2 diabetes. Nat Genet 2000;

26:76–80[CrossRef]

ink_type=DOI> [Medline]

ype=MED>

7. Jamain S, Quach H, Betancur C, Rastam M, Colineaux C, Gillberg

IC, Soderstrom H, Giros B, Leboyer M, Gillberg C, Bourgeron T:

Mutations of

the X-linked genes encoding neuroligins NLGN3 and NLGN4 are

associated with

autism. Nat Genet 2003; 34:27–29[CrossRef]

link_type=DOI> [Medline]

ype=MED>

8. Weiss LA, Shen Y, Korn JM, Arking DE, DT, Fossdal R,

Saemundsen E, Stefansson H, Ferreira MA, Green T, Platt OS, Ruderfer

DM,

Walsh CA, Altshuler D, Chakravarti A, Tanzi RE, Stefansson K,

Santangelo SL,

Gusella JF, Sklar P, Wu BL, Daly MJ, the Autism Consortium:

Association

between microdeletion and microduplication at 16p11.2 and autism. N

Engl J

Med 2008 (Epub ahead of print)

9. Owen MJ, Craddock N, Jablensky A: The genetic deconstruction of

psychosis. Schizophr Bull 2007; 33:905–911[Abstract/Free Full Text]

& resid=33/4/905>

10. Malaspina D, Corcoran C, Fahim C, Berman A, Harkavy-Friedman J,

Yale S, Goetz D, Goetz R, Harlap S, Gorman J: Paternal age and

sporadic

schizophrenia: evidence for de novo mutations. Am J Med Genet 2002;

114:299–303[CrossRef]

01 & link_type=DOI>

ype=MED>

11. Straub RE, Lipska BK, Egan MF, Goldberg TE, Callicott JH, Mayhew

MB, Vakkalanka RK, Kolachana BS, Kleinman JE, Weinberger DR: Allelic

variation in the GAD1 (GAD67) is associated with schizophrenia and

influences cortical function and gene expression. Mol Psychiatry 2007;

12:854–869[CrossRef]

001988 & link_type=DOI>

ype=MED>

12. GAIN Collaborative Research Group: New models of collaboration

in genome-wide association studies: the Genetic Association

Information

Network. Nat Genet 2007; 39:1045–1051

link_type=DOI> [Medline]

ype=MED>

FAIR USE NOTICE: This may contain copyrighted (© ) material the use

of which

has not always been specifically authorized by the copyright owner.

Such

material is made available for educational purposes, to advance

understanding of human rights, democracy, scientific, moral, ethical,

and

social justice issues, etc. It is believed that this constitutes

a 'fair

use' of any such copyrighted material as provided for in Title 17

U.S.C.

section 107 of the US Copyright Law. This material is distributed

without

profit.