Shackman Psyc210 Module11 NatureNurture Part2

7/21/2019 Shackman Psyc210 Module11 NatureNurture Part2

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We wish to suggest a structure forthe salt of deoxyribonucleic

acid...This structure has novelfeatures which are of considerablebiological interest...It has not escapedour notice that the specic pairing wehave postulated immediatelysuggests a possible copying

mechanism for the genetic material

Watson & Crick Nature 1953


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we should remain unabashed about theultimate [goal] of genomic medicine which[is] to transform the health of our children

and our children!s children

LanderNature 2011


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Plan for Today

Lecture on Nature & Nurture, Part 2 The genomics revolution

Part of the motivation is to educateyou

as citizens, taxpayers, and

healthcare consumers

Take-home critical thinkinguestions


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P!"# 2$%The nature & nurture of T&P, Part 2

Molecular substrates of trait-like dierences with a focus onGene-Environment Interactions

AJ Shackman

March 2015


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#onceptual 'oadmapT&P are some(hat herita)le*

hat molecular mechanisms account forthat heritabilit!"

T&P re+ects the in+uence of )oth geneticinheritance nature and theenvironment.experience nurture*

#re these se$arate eects %G and E or aninteraction %G ' E"

e()(, E'$osure to stress and *risk!+ )enes


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#re these se$arate eects %G and E or aninteraction %G ' E"

e()(, E'$osure to stress and *risk!+ )enes


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#re these se$arate and inde$endent eects

%G and E or an interaction %G ' E"

e()(, *isk!+ )enes #. stress e'$osure


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"N#

/uick 0enetics Primer

$enes


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- 1Nis orani!ed into chromosomes" the #ectors o$heredit%

- uman ce''s ha#e 23 (airs o$ chromosomes )*+ , ce''-"one (air .descended/ $rom mom and one $rom dad

1N #hromosomes

h


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- 1Nis orani!ed into chromosomes" the #ectors o$heredit%

- uman ce''s ha#e 23 (airs o$ chromosomes )*+ , ce''-"one (air .descended/ $rom mom and one $rom dad

1N #hromosomes


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hat about )enes"

htt(s,,eniki(ediaor,iki,umaneno

0


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- 0enea reion o$ 4NA,NA se6uence" corres(ondinto a unit o$ inheritance or sin'e 7asic instruction

).reci(e/-

- 3uman genome821"00023"000 enes

- :enes ho'd the in$ormation to 7ui'd and maintain an

oranism;s ce''s and (ass enetic traits to o


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).reci(e/-

- 3uman genome822"000 (roteincodin enes




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).reci(e/-

- 3uman genome822"000 (roteincodin enes




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hat makes usdierent"

ll l 5 di id l 1i6


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- llelea #ariant o$ a ene ).enetic (o'%mor(hism/-

- 4i


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- 4i


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- 4i


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- 4i


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- !NPsin'e nuc'eotide (o'%mor(hism )so" a (articu'arkind o$ a''e'e-

- 1030 mi''ion SN?s in humans )810M .common/ @1B$re6uenc%-

- Most common t%(e o$ se6uence#ariation )90B tota' #ariation-

!NP7s 4 5ndividual 1i6erences

!NP7 5 di id l 1i6


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- !NPsin'e nuc'eotide (o'%mor(hism )so" a (articu'arkind o$ a''e'e-

- 820 mi''ion SN?s in humans )810M .common/ @1B$re6uenc%-

- Most common t%(e o$ se6uence#ariation )90B tota' #ariation-

!NP7s 4 5ndividual 1i6erences


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/ow mi)ht we tr! to discover the alleles that $redicttrait-like dierences in T&P %, E, 0or intermediate $henot!$es %e()(, am!)dala activation"


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1et+s start with asim$lied e'am$le3


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?atients )DCasesE-

A''e'e F1 9

A''e'e F2 1

B A''e'e F1 90B

(,,#assarstatsnet,odds2=2htm'


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?atients )DCasesE- Contro's

A''e'e F1 9 1

A''e'e F2 1 9

B A''e'e F1 90B 10B

(,,#assarstatsnet,odds2=2htm'


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?atients )DCasesE- Contro's

A''e'e F1 9 1

A''e'e F2 1 9

B A''e'e F1 90B 10B

llele 8$ is associated(ith a 9x increased riskof disease:;risk ratio7

arstatsnet,odds2=2htm' )090 a''e'e F1 G (atients> 010 a''e'e F2 G (atient> 090,010 G 9 -


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ow we need to scale this u$3

0


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- 0


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- 0


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/ow the heck are we )oin) toe4cientl! measure 56M 7P+s"

!NP #hip


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!NP #hip

etai's Are Not Hm(ortant

!NP #hip


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!NP #hip


!NP #hip


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!NP #hip

?ragment of one strand


!NP #hip


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!NP #hip


@inds (ith complement


!NP #hip


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!NP #hip



rray of pro)es fordi6erent gene variants


!NP #hip


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!NP #hip




Aeasure )inding


!NP #hip


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!NP #hip




Aeasure )inding



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0


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- Irute $orce a((roachtestin one7% one thecorre'ation 7eteen traits and hundreds o$ thousands

o$ common enetic #ariants

- :WAS treats e#er% common enomic #ariant the same"a''oin the disco#er% o$ no#e' trait or diseasere'e#ant enetic #ariants in the a7sence a priori

h%(otheses

- he o((osite o$ .candidate ene/ studies that uti'i!etheories to test a sma'' num7er o$ enetic #ariants

- ?ena't% is 'o statistica' (oer and sensiti#it%" due tocorrection $or mi''ions o$ tests across the enome

-

Kurthermore" :WAS i'' miss rare enetic #ariants7ecause the% are not inc'uded on the SN? chi( arra%s

0


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h%(otheses


- ?ena't% is 'o statistica' (oer and sensiti#it%" due tocorrection $or mi''ions o$ tests across the enome

- Kurthermore" :WAS i'' miss rare enetic #ariants7ecause the% are not inc'uded on the SN? chi( arra%s

0


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h%(otheses


- ?ena't% is 'o statistica' (oer and sensiti#it%" due tocorrection $or mi''ions o$ tests across the enome)(05 (05,1"000"000-

- Kurthermore" :WAS i'' miss rare enetic #ariants

0


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h%(otheses


- ?ena't% is 'o statistica' (oer and sensiti#it%" due tocorrection $or mi''ions o$ tests across the enome)(05 (05,1"000"000-

- Kurthermore" :WAS i'' miss rare enetic #ariants

0


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h! bother"

The Premise


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g>, N, =, and !#> !o it7s diBcult to generate good hypotheses candidategenes to examine>

5f (e could someho( harness genetics to understand the molecularneuro)iology of T&P and associated psychiatric disorders, it (ould ena)le usto

- edene dianostic cateories and &? traits in terms o$ 6uantia7'e etio'o% )rootcauses-

- 4e#e'o( no#e' treatments or (re#ention e


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The Premise


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Cery recent 0g>, F2G variation in A11 phenotype can )eexplained )y individual polymorphisms genes

- Suests that a su7stantia' (ro(ortion o$ enetic#ariation resu'ts $rom #er% 'are num7ers o$ sma''e


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- Hn enera'" recent ork suests that most enetic#ariation resu'ts $rom #er% 'are num7ers o$ sma''e


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8ut there+s a $otential$roblem3

The Pro)lem of !mall =6ects


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- Common (o'%mor(hisms ha#e" at most" eak e


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had!a mean small eects"

he #ase of 3eight


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he #ase of 3eight

he #ase of 3eight


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eiht is hih'% herita7'e )8U5B- and hih'% (o'%enic"

ith man% #ariants contri7utin and there$ore sma''e


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eiht is hih'% herita7'e )8U5B- and hih'% (o'%enic"

ith man% #ariants contri7utin and there$ore sma''e


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To $ut 9 mm %$er variant in $ers$ective

he #ase of 3eight

on% Stark )5 $eet-Xs

I'ack Wido )525$eet-

G 15 cm G 150 mm

G 35

(o'%mor(hisms


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Millimeters" hat about )oodold fashioned inches"


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1 inch G 25* mm G

+* a''e'ic #ariants


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hat about T&P"


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ontrast to heiht and (s%cho(atho'o%" :WAS studies o$ &? ha#e re'ied on ma''er sam('es

Moor used a disco#er% sam('e o$ disco#er% sam('es o$ N G 1" 35

#ice had a disco#er% sam('e o$ N G 11"000

sur(risin'%" the% 'acked the (oer to detect a sin'e enetic #ariant that asnicant'% associated ith di


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Moor et a' N G 1" 35 Ser#ice et a' N G 11"000

sur(risin'%" the% 'acked the (oer to detect a sin'e enetic #ariant that as

nicant'% associated ith di


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#re small eects a bi) $roblem"

Is the e'$enditure worth it"

Tin! Eects 0an 8e


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Me%er et a' Ame

Tin! Eects0an 8ePracticall! Im$orta


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Tin! Eects 0an 8e


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er ?s%cho' 1990> :reena'd et a' J?S? in (ress> 7ut see a'so Keruson e# :en ?s%cho' 2009


se of sprin

cia' meetin he'd 4ecem7er 1U" 19U" it as decided to end (remature'% a ran

7'ind e=(eriment )nG22'- on the e


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se of sprin




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se of sprin




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e Point*

cts can )e very practically important (hen they are cumulated over m

viduals e>g>, the population of nations

vidual experiences e>g>, many Eo) applications, in the case of discrimi


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hat about more directevidence"

mall Eects, 8i) Thera$eutic


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mall Eects, 8i) Thera$euticIm$act

Lander Nature 2011> ?a(assotiro(ou'os iCS 2



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0.0 2:6: .ata

;6 in < deaths




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#holesterol is a strong predictor of heart disea

N G 900"000 su7ects> Lancet 200




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#holesterol is a strong predictor of heart disea 1 mmo',L 'oer tota' cho'estero' G 50B

reduction in morta'it% at mid'i$e

Cho'estero' ums u( %our arteries

N G 900"000 su7ects> Lancet 200




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3eart 1isease 'isk is 5nherited Cho'estero' is a7out 50B herita7'e Mo'ecu'ar (atha%sP

0


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, ) $Im$act


0


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, ) $Im$act


0


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, ) $Im$act


0


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, ) $Im$act

Ine of the 9J loci 4 3A0#' M:C (redicts modest #ariance in cho'estero' 2U m,d'

Iut the (atha% coded 7% this 'ocus is the taret o$ the

Statins" the most (o(u'ar dru $or reducin cho'estero'

Amon the 7est se''in dru in histor% )Z12*I in .05- C'inica''% e ?a(assotiro(ou'os iCS 2



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, ) $Im$act

Ine of the 9J loci 4 3A0#' M:C (redicts modest #ariance in cho'estero' 2U m,d'

Iut the (rotein coded 7% this 'ocus is the taret o$ the

Statins" the most (o(u'ar dru $or reducin cho'estero'

Amon the 7est se''in dru in histor% )Z12*I in .05- C'inica''% e ?a(assotiro(ou'os iCS 2



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, ) $Im$act

Take 3ome Points We ust disco#ered 9* other SN?s Lots o$ o((ortunities $or understandin the mo'ecu'ar

mechanisms under'%in one o$ the 7iest ki''ers

More enera''% T sma'' e ?a(assotiro(ou'os iCS 2


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ow !ou mi)ht be sa!in) to !ourself,

I+m a scal conservative, what is this costin) me and other ta'$a!ers"

#re these )enetic discoveriesworth it"

The 0ost of G#7s= Is it orth It""



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The 0ost of G#7s= Is it orth It""- H$ e assume that the :WAS resu'ts )descri7ed in our

re#ie- reYect a tota' o$ 500"000 SN? chi(s [Z500,chi( G Z250M

- 82"000 #ariants detected in hih6ua'it% 7iomedica'studies )across a #ariet% o$ (h%sica' and menta'

disorders-

- Z125"000 (er disco#ered #ariant

-

:ood in#estmentP

- Z250M- 12 stea'th hter ets- Much 'ess than a sin'e na#% su7marine

- Kraction o$ the 8Z9 7i''ion cost o$ the Lare adronXisscher et a' 201




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The 0ost of G#7s= Is it orth It""- Ieen estimated that a'' the hih6ua'it% :WAS studies

)circa 2012- reYect a tota' o$ 500"000 SN? chi(s [Z500,chi( G Z250M

- 4etected 82"000 enetic #ariants across a #ariet% o$(h%sica' and menta' disorders

- Z125"000 (er ne'% disco#ered #ariant

- :ood in#estmentP

- Z250M- 12 stea'th hter ets- Much 'ess than a sin'e na#% su7marine- Kraction o$ the 8Z9 7i''ion cost o$ the Lare adron

Co''ider Xisscher et a' 201




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- :ood in#estmentP






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- :ood in#estmentP Judment ca''






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- :ood in#estmentP Judment ca''




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Perha$s a dierentstrate)! would be hel$ful"

Aain =6ects and 5nteractions


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- raditiona' :WAS a((roaches assumethat indi#idua' enes direct'% determine(henot%(es )&?" disorders-


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8ut what if traits and disorders re>ectthe interaction of Genes and E'$erience"

hat if we inherit a $redis$osition to be neurotic, e'troverted, or conscientious,)iven the a$$ro$riate environment"

0-= 5nteractions 0 x =


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- raits c'uster in $ami'ies )remem7er 4raco Ma'$o%-

- Iut herita7i'it% a((ears to 7e (ro7a7i'istic and (articu'ar$ami'% mem7ers ma% not inherit a (articu'ar trait )e" hih'e#e's o$ .e#i'ness"/ se'$contro'" or de(ression-

- Neither enetics nor en#ironment is so'e'% res(onsi7'e $or(roducin trait'ike di


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0an a$$l! this lo)ic to )enehuntin)

0-= 5nteractions 0 x =


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ch for combinations of )enes %those contributin) to skin $i)mentationronments %e'$osure to sunli)ht that $redict outcomes of interest


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- ?amily #on+ictHndi#idua's ho are enetica''% (redis(osed-to 'o C,SC are e#en moreim(u'si#e in a conYictua' $ami'% en#ironment>

- Aarriage and 'eligiosityHndi#idua's ho are enetica''% (redis(osed to su7stancea7use are 'ess 'ike'% to de#e'o( drinkin (ro7'ems i$ the% ere married or re'iious>:ene\Marriae a'so $ound $or M44

- Lo( Parental Aonitoring and !u)stance-)using PeersHndi#idua's ho areenetica''% (redis(osed to su7stance use and antisocia' 7eha#ior are more 'ike'% tode#e'o( (ro7'ems in these en#ironments

5n short, a (ide variety of environmental factors can

)a- trier")b- com(ensate $or" or)c- enhance enetic (redis(osition


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)a- trier")b- com(ensate $or" or)c- enhance

particular genetic predispositions


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hat about molecular )enetics%7Ps"

?amous 5llustration


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Cas(i et a' Science 200monoamine o=idase A

?amous 5llustration


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.o )enes interact with maltreatment to $redictantisocial behavior"

.o alleles chan)e the slo$e relatin) maltreatment

?amous 5llustration


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?es@ #bused kids with the *)ood+ allele%)ra! showed fewer antisocial behaviors 3$rotective

econd ?amous 0= =xample


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Cas(i et a' Science 2003" Amer J ?s%chiatr% 2010> Monroe ?s%cho' S

#aspi 1uke



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#aspi 1uke




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#aspi 1uke


.oes the im$act of stress on de$ressionde$endon the serotonin trans$orter %A-/TT )ene"



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#aspi 1uke


!hort Long

?es@ 0arriers of the 7hort allele showed astron) $ositiverelationshi$ between life stress andde$ression B 7hort allele confers risk %or the

1on allele confers rotection


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Ce! Take /ome Points

1 &? h h i 7'

Oey Take 3ome Points for Today7sAeeting


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1 &? are somehat herita7'e2 We can use :WAS )SN? chi(s- to search the enome )10M

common #ariants- $or the SN?;s that account $or that herita7i'it%3 he (remise o$ this enomic a((roach is nothin short o$re#o'utionar% We remain 'are'% inorant a7out the 7io'oica'under(innins o$ &? :WAS (ro#ide a (oer$u' too' $ordisco#erin the mo'ecu'ar oriins o$ &? edene &? and associated disorders in terms o$ root

causes instead o$ se'$re(orted s%m(toms 4e#e'o( no#e' screenin (rocedures and inter#entions

rounded in an understandin o$ under'%in mechanisms)etio'o%-

* Irute $orce a((roach ?ena't% is 'o statistica' (oer due to

correction $or mi''ions o$ tests)(05 #s (05,1"000"000-5 erita7'e traits reYect the inYuence o$ man% SN?/s )(o'%enic-"

each ith a #er% sma'' e


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Sma'' e


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Sma'' e


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Sma'' e


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Sma'' e


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To be continued3

Genome Traits %Evildoin)Intermediate Phenot!$e

/uestions


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ontinued3

1 ?ick an% one o$ the $undamenta'6uestions a7out &? that e ha#e

/uestions


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co#ered in c'ass since the start o$ thesemester )e" hat are the $undamenta'dimensions o$ &?- and then 7rieY%discuss ho enetic in$ormation cou'd(ro#e he'($u' $or addressin that 6uestion

2 Ht a((ears 'ike'% that enomics i'' ('a%an increasin ro'e in medicine" and hence

is 'ike'% to ha#e a direct im(act on %ouand %our 'o#ed ones )direct'%" as(artici(ants in a (u7'ic hea'thcares%stem" or as ta=(a%ers $undin &4-Hdenti$% one a% in hich the enomicsre#o'ution cou'd inYuence %ou )e"screenin" (recision medicine- and

discuss hether this is a (ositi#e orneati#e thin Oou ma% nd it he'($u' tos(end a 'itt'e time on Wiki(edia)htt(s,,eniki(ediaor,iki,Hntroduction

toenetics-

ontinued3


/uestions


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co#ered in c'ass since the start o$ thesemester )e" hat are the $undamenta'dimensions o$ &?- @rie+y discuss ho(genetic information could provehelpful for addressing that uestion




toenetics-

ontinued3


/uestions


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toenetics-

ontinued3


/uestions


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is 'ike'% to ha#e a direct im(act on %ouand %our 'o#ed ones )direct'%" as(artici(ants in a (u7'ic hea'thcares%stem" or as ta=(a%ers $undin &4-5dentify one (ay in (hich thegenomics revolution could in+uenceyou and discuss (hether this is a

positive or negative thing> Oou ma%nd it he'($u' to s(end a 'itt'e time onWiki(edia)htt(s,,eniki(ediaor,iki,Hntroduction

toenetics-

ontinued3

3 Hn March 2015" researchers at Wei'' Corne'' shoed ^that a sin'enuc'eotide(o'%mor(hism )SN?- in the $att% acid amide h%dro'ase )KAA- ene o$ the

d 7i id h '' ' ' ' ' d 7 h i ' < i 7 h

/uestions


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endocanna7inoid s%stem has (ara''e' mo'ecu'ar" neura' and 7eha#iora' e


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A#ai'a7'e [htt(,,n%timescom,2015,03,0U,o(inion,sunda%,the$ee'oodenehtm'PrG0

he author notes that

^Kor the rst time" scientists ha#e demonstrated that a enetic #ariation in the 7rainmakes some (eo('e inherent'% 'ess an=ious" and more a7'e to $oret $ear$u' andun('easant e=(eriences his 'uck% enetic mutation (roduces hiher 'e#e's o$

anandamide the soca''ed 7'iss mo'ecu'e and our on natura' mariuana in our7rains Hn short" some (eo('e are (rone to 7e 'ess an=ious sim('% 7ecause the% onthe enetic see(stakes and random'% ot a enetic mutation that has nothin at a''to do ith strenth o$ character^

A 7'oer at Scientic American

A#ai'a7'e [ o7ected to 7oth the essa% and the stud%" notin that

^Kriedman/s @essa% is" in e


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A 7'oer at Scientic American

A#ai'a7'e [ o7ected to 7oth the essa% and the stud%" notin that



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Iut a 7'oer at )cientic #merican

A#ai'a7'e [ htt(,,7'osscienticamericancom,crosscheck,2015,03,13,n%timesh%(eo$$ee'oodenemakesme$ee'7ad, o7ected to 7oth the essa% and the stud%" notin that



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Iut a 7'oer at )cientic #merican

A#ai'a7'e [ htt(,,7'osscienticamericancom,crosscheck,2015,03,13,n%timesh%(eo$$ee'oodenemakesme$ee'7ad, o7ected to 7oth the essa% and the stud%" notin that



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ake a c'oser 'ook at the 3 documents Comment on an% o$ the $o''oin issues

Strenths and 'imitations o$ the stud% Sam('e si!e Kocus on homo'oous 7eha#iora' and 7rain (henot%(es )DmarkersE- in 2

s(ecies ?rocedures $or mani(u'atin and measurin an=iet% Were the authors a((ro(riate'% circums(ect and so7er in their discussion

o$ the stud%/s (otentia' im('ications" or did the% o#erreachP

Strenths and eaknesses o$ the N3 Times essa% )]#erse''inP 4um7eddonP-

Strenths and eaknesses o$ the )cientic #mericanre7utta' )oo 6uick todismissP 4idn/t et the #a'ue o$ com7inin mechanistic mode's in rodents ithnonin#asi#e measures o$ emotiona' e=(erience and neuro(h%sio'o% in

humans-

he a( 7eteen science" the media )NO imes,Scientic American-" and the(u7'ic What ets 'ost in trans'ationP

ontinued3


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ake a c'oser 'ook at an% o$ the 3 documents Comment on an% o$ the $o''oin issues

Strenths and 'imitations o$ the stud% Sam('e si!e Kocus on homo'oous 7eha#iora' and 7rain (henot%(es )DmarkersE- in 2

s(ecies ?rocedures $or mani(u'atin and measurin an=iet% Were the authors a((ro(riate'% circums(ect and so7er in their discussion

o$ the stud%/s (otentia' im('ications" or did the% o#erreachP

Strenths and eaknesses o$ the N3 Times essa% )]#erse''inP 4um7eddonP-

Strenths and eaknesses o$ the )cientic #mericanre7utta' )oo 6uick todismissP 4idn/t et the #a'ue o$ com7inin mechanistic mode's in rodents ithnonin#asi#e measures o$ emotiona' e=(erience and neuro(h%sio'o% in

humans-

he a( 7eteen science" the media )N3 Times%)cientic #merican-" and the(u7'ic What ets 'ost in trans'ationP

ontinued3


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Time-Permitting'evie( /uestions

&? reYect


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A NatureI Nurture

C Ioth

:enes )nature- can inYuence


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A n#ironmentsand e=(erience

I Neither Nature

and nurture aredistinct andinde(endent

$orces

Nature )herita7i'it%- is


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A Ki=ed andimmuta7'e

I ?'astic and can

chane inres(onse toroin

autonom% ordue tocumu'ati#eim(act

erita7i'it% is


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A he (ro(ortiono$ #ariation in atrait" such as

C,SC" that isaccounted $or 7%the (ediree)$ami'% tree-

I ?X,:X

C A and I

stimates o$ herita7i'it%


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A Are =edI Can 7e inYuenced 7%

socia' anden#ironmenta'inYuences )e" 'i#inin a conser#ati#ere'iious communit%-that increase ordecrease the amount

o$ #ariation in the trait)e" disinhi7ition"(art%in" smokin-

erita7i'it%


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A Hs the B o$#ariation in a trait"such as ,?" thatis (assed don

$rom %our (arentsI eYects the

inheritance o$

enes" not(henot%(es ortraits

erita7i'it% descri7es


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Ahe B o$ m% trait thatis inherited )nature-#s en#ironmenta')nurture-

Ihe B o$ (henot%(ic#ariation across arou( o$ indi#idua'sthat is inYuenced 7%enetic $actors

C Hndi#idua's ithin a(o(u'ation )e" A'e=-

ih'% herita7'e traits" such asheiht


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A Are our destin%I Can (otentia''%

7e (oer$u''%

inYuenced 7%inter#entions)en#ironment-


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The =nd

Things to #onsider dding


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Somatic mosaicism 4NA di


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E'tra 7lides

$> 'ecap environment.nurtureM

fe( interim take home points


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2> There is a considera)le excitement a)out so-called neurogeneticapproaches that com)ine measures of molecular geneticvariation !NPs (ith measures of )rain function fA'5>


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hat about the brain"

Genome Traits %Evildoin)Intermediate Phenot!$e


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@ogdan


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ddress ho( genes in+uence )ehavior U remem)er, herita)ility does not

address )iological mechanism: 7% corre'atin enetic #ariation ith intermediate 7io'oica' (henot%(es )e"

am%da'a acti#ation-" e can disco#er testa7'e mechanisms $or enetic inYuenceon 7eha#ior

ddress the molecular mechanisms linking genes to )rain to )ehavior it/s hard to direct'% measure neurochemistr% )e" serotonin 'e#e's in the

am%da'a- in humans

H$ e measure a enetic (o'%mor(hism ith a knon $unction )e" serotonintrans(orter SN?-

and e are i''in to make some assum(tions )di


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can address 6uestions such as" Why is the amygdala hyper(reactive inbehaviorally inhibited individuals6

Potentially address the molecular mechanisms linking genes to )rain to)ehavior

it/s hard to direct'% measure neurochemistr% )e" serotonin 'e#e's in the

am%da'a- in humans

H$ e measure a enetic (o'%mor(hism ith a knon $unction )e" serotonintrans(orter-



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am%da'a- in humans




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am%da'a- in humans




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am%da'a- in humans




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(o'%mor(hic reion )5L?- on the SLC+A* ene

- K! allele is )ad Hndi#idua's ith the 'esstranscri(tiona''%ebcient short a''e'e )$eer trans(orter(roteins a#ai'a7'e to c'ear serotonin $rom the s%na(se-sho heihtened threatre'ated am%da'a reacti#it%re'ati#e to indi#idua's ith the 'on a''e'e

- 0ene mygdalaMetaana'%ses suest that the5L? enot%(e accounts $or 25 o$ the #ariance in

am%da'a reacti#it%

- 0ene mygdala A11 #idence that theseenetica''% con$erred di


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- K! allele is )ad Hndi#idua's ith the 'esstranscri(tiona''%ebcient short a''e'e )$eer trans(orter(roteins a#ai'a7'e to c'ear serotonin $rom the s%na(se-sho heihtened threatre'ated am%da'a reacti#it%re'ati#e to indi#idua's ith the 'on a''e'e

- 0ene mygdalaMetaana'%ses suest that the5L? enot%(e accounts $or 25 o$ the #ariance in

am%da'a reacti#it%



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- K! allele is )ad Hndi#idua's ith the 'esstranscri(tiona''%ebcient short a''e'e )$eer trans(orter(roteins a#ai'a7'e to c'ear serotonin $rom the s%na(se-sho heihtened threatre'ated am%da'a reacti#it%re'ati#e to indi#idua's ith the 'on D7E a''e'e

- 0ene mygdalaMetaana'%ses suest that 5L? accounts $or 25B o$ the #ariance in am%da'a

reacti#it%



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- K! allele is )ad Hndi#idua's ith the 'esstranscri(tiona''%ebcient short a''e'e )$eer trans(orter(roteins a#ai'a7'e to c'ear serotonin $rom the s%na(se-sho heihtened threatre'ated am%da'a reacti#it%re'ati#e to indi#idua's ith the 'on D7E a''e'e

- 0ene mygdalaMetaana'%ses suest that 5L? accounts $or 25B o$ the #ariance in am%da'a

reacti#it%



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V0=N=T5# I@!='CT5INW5L?

V!!APT5INWreduced ebcac% o$ 5 )(rotein-

V!!APT5INWtoo much 5 in am%da'a s%na(ses)chemistr%-

VN='L I@!='CT5INWincreased am%da'areacti#it% to threat

V=P51=A7L I@!='CT5INWM44" es(ecia''% amonindi#idua's e=(osed to stress

e Pro)lem of ssumptions


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No relation )et(een polymorphism and amygdalarJ3TT expression(hen you actually go in and measure thetransporter using P=T

Dour ndins are in areement ith the maorit% o$human ? studiesQthat suest there is not aQdetecta7'e re'ationshi( 7eteen in vivo 5 7indinand sa''e'e carrier statusQ our ork in the rhesus

monke and that o$ others in humans ca''s into uestion

Oalin


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@rief side on 3o( the =nvironment0ets nder the !kin

7tudents=

what+s a $lausible mechanism"

/ow mi)ht $arentin) or e'$osure to other risks in>uence behavior %$henot!$e"

=pigenetics provides a )iological explanation for ho( = parenting, therapy, lifeevents alters )ehavior

- he en#ironment )e" 'earnin" stress- can a'ter ene e=(ression )(rotein s%nthesis-ith t 't i th )4NA h t h it 7' -

3o( 1oes = 0et nder the !kinM


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ithout a'terin the enome )4NA> hence" not herita7'e-

- :ene e=(ression is inYuenced 7% transcri(tion $actors" hich 7ind to se6uences o$ 4NA

- Iindin o$ transcri(tion $actors turns enes on or o accordin'%" there must 7e a mechanism here7%

di


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di


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di


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P!"# Q$2 '%S@

G-E 0orrelations=/ow Genes Get Dutside the 7kin

AJ Shackman

9 4ecem7er 2013


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P!"# Q$2 '%S@

G-E 0orrelations=/ow Genes Get Dutside the 7kin

7tudents"


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Lemery !

Xa6ee Penn

Aany sources of in+uence that (e might consider Kenvironmental are actuallynon-random and genetic

$ Passive 0-= correlation nature and nurture are confounded

-

;RR


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$> Passive 0-= correlation nature and nurture are confounded-

amon 7io'oica''% re'ated (arents and o =vocative 0-= correlation- e" a chi'd ho is (redis(osed to ha#in an outoin" cheer$u' &? is more 'ike'% to

e#oke (ositi#e attention $rom others than a chi'd ho is (redis(osed to N,N

- " Hndi#idua's ith a rum(%" a7rasi#e tem(erament )N,N- tend to e#okeun('easant res(onses

$rom coorkers and others than cheer$u'" $riend'% indi#idua's

F> ctive 0-= correlation- Hndi#idua's acti#e'% se'ect en#ironments- " indi#idua's (redis(osed to hih ,? seekin ma% 7e more (rone to attend

(arties" o to 7ars" meet ne (eo('e" 7e e=(osed to or to tr% su7stances o$ a7use


-

;RR


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$> Passive 0-= correlation nature and nurture are confounded- amon 7io'oica''% re'ated (arents and o =vocative 0-= correlation

- e" a chi'd ho is (redis(osed to ha#in an outoin" cheer$u' &? is more 'ike'% toe#oke (ositi#e attention $rom others than a chi'd ho is (redis(osed to N,N

- " Hndi#idua's ith a rum(%" a7rasi#e tem(erament )N,N- tend to e#okeun('easant res(onses

$rom coorkers and others than cheer$u'" $riend'% indi#idua's

F> ctive 0-= correlation- Hndi#idua's acti#e'% se'ect en#ironments- " indi#idua's (redis(osed to hih ,? seekin ma% 7e more (rone to attend

(arties" o to 7ars" meet ne (eo('e" 7e e=(osed to or to tr% su7stances o$ a7use


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-

;RR


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$> Passive 0-= correlation nature and nurture are confounded- amon 7io'oica''% re'ated (arents and o =vocative 0-= correlation- e" a chi'd ho is (redis(osed to ha#in an outoin" cheer$u' &? is more 'ike'% to

e#oke (ositi#e attention $rom others than a chi'd ho is (redis(osed to N,N

- " Hn$ant 7eha#iora' inhi7ition e#okes (arenta' insensiti#it%" hich then(otentiates

ma'ada(ti#e (arentTchi'd interactions o#er time" e=acer7atin $ear o$ no#e't%

F> ctive 0-= correlation Niche @uilding- Hndi#idua's acti#e'% se'ect en#ironments

- " indi#idua's (redis(osed to hih ,? seekin ma% 7e more (rone to attend(arties" o to 7ars" meet ne (eo('e" 7e e=(osed to de'in6uent (eers" and tr%

=vidence for 0-= #orrelations


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Aostly from ?T studies demonstrating that Kenvironmental measures areherita)le, including many linked to psychopathology

e"marita' 6ua'it%" socia' su((ort" (arenta' disci('ine,armth" $ami'% en#ironment"

=vidence for 0-= #orrelations


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(eer re'ationshi(s" neati#e 'i$e e#ents such as di#orce and e=(osure to trauma

=nvironments are herita)le )ecause genotype in+uences )ehaviors that evoke,select, and modify features of the environment

n#ironments 'ess amena7'e to 7eha#iora' modication are 'ess herita7'e" e" thedeath o$ a 'o#ed one" 'osin one/s home in a natura' disaster

han those that de(end on the indi#idua'/s 7eha#ior" e" di#orce" ettin red

Take home :enetic risk $actors do not necessari'% ha#e direct e


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Take home :enetic risk $actors do not necessari'% ha#edirect e


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7io'oica' (atha%

his i'' occur on'% i$ the enetic under(innins o$ the disorder reYect a hihderee o$ etio'oica' homoeneit% ie a sin'e disease (rocess)De6uina'it%E-

Hntermediate scenarios )neither V'% nor :ood- are (ossi7'e

There are many many (ays to make a neuron hypofunction)shrunkendendrites" too $e or d%s$unctiona' rece(tors" donreu'ated 2ndmessener s%stems" or decient trans(ort mechanisms

Long Term Prospects, The gly


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There are even more path(ays to make a complexcircuit dysfunction

his scenario is 'ike'% i$ there are hundreds o$ distinct 7iochemica'chanes that indi#idua''% contri7ute to 4= )neither necessar% nor

subcient- ith inde(endent (atha%s to the (henot%(e

?erha(s there are too man% a%s $or the human 7rain to (roduces%m(toms,sins o$ (s%chiatric disorders )$or e=am('e" sad mood" auditor%ha''ucinations" randiosit%- $or a 'imited num7er o$ 7io'oica''% coherent(atha%s to emere $rom the 100/s or 1000/s o$ enes that make sma''

contri7utions to risk

ere" (s%chiatric disorders )or &?- arise at such a hih 'e#e' ithin themindT7rain s%stem that e ha#e no a% to interate :WAS or se6uencinndins

.

1 here is considera7'e e=citement a7out the neuroenetics a((roach

2 his reYects 7oth c'inica' interests )=- as e'' as the 7asic science ho(e that it can(ro#ide c'ues a7out the mo'ecu'ar di


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%

3 Iut assum(tions ma% not 7e arranted> e" 5L? is unre'ated to trans(ortere=(ression in am%da'a

* Neuroeneticists $ace a'' o$ the (ro7'ems out'ined 7% end'er The 8ro5en $lass" and"The 9et :echanic. No uarantee that there are a 'imited num7er o$ $unctiona''% coherentsu7strates to 7e identied

5 he e


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etc-

"ou could target them for precision interventions @=?I'= the onset of cumulativedamage

in e


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he (henot%(e )&?,4=- reYects the cumu'ati#e e traits are massi#e'% D(o'%enicE

Aore !ophisticated pproaches0ene0ene & Aultilocus ProDles


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Hn (rinci('e" it ou'd 7e he'($u' to mode' ene\eneinteractions or de#e'o( more com('e= additi#e )man% maine


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Hn (rinci('e" it ou'd 7e he'($u' to mode' ene\eneinteractions or de#e'o( more com('e= additi#e )man% maine


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@ogdan


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-inso$ar as e 7e'ie#e )e" the materia' co#ered in(rior 'ectures- that (s%cho(atho'o% and &? reYectthe interaction o$ enetica''% endoed diathesesand neati#e 'i$e e#ents )e" stress" ad#ersit%"a7use" 'oss- and 'earnin

- and not the direct conse6uence or main e


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1 here is considera7'e e=citement a7out the neuroenetics a((roach

2 his reYects 7oth c'inica' interests )=- as e'' as the 7asic science ho(e that it can(ro#ide c'ues a7out the mo'ecu'ar di


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3 Iut assum(tions ma% not 7e arranted> e" 5L? is unre'ated to trans(ortere=(ression in am%da'a

* Neuroeneticists $ace a'' o$ the (ro7'ems out'ined 7% end'er The 8ro5en $lass" and"The 9et :echanic. No uarantee that there are a 'imited num7er o$ $unctiona''% coherentsu7strates to 7e identied

5 he e


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Hn cases here there is an interaction 7eteen :enes )in areate- and n#ironment )e"(eer de'in6uenc% e=(osure-" that is" Da hitE in the KA 'iterature

Ht makes sense to dri'' don into s(ecic enes" either candidate #ariants or :WAS

$> 'ecap environment.nurtureM

2>


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parameterM g>, T&P to distinct neuro)iological systemsM

J> There is a considera)le excitement a)out so-called neurogeneticapproaches that com)ine measures of molecular geneticvariation !NPs (ith measures of )rain function fA'5>


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2. Two major types of genomic variants

1. Sequence variants


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-SNPs-single insertions & deletions

2. Structural variants (major categories)

-tandem repeats (also called microsatellites)-triplet repeats (also called minisatellites)

-N!s (cop" num#er variants)$ to #e

discussed soon

The genome


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F>$-F>2)illion )ases

Y2$-2F,%%%genes

The most common type of geneticvariantthe SNP

!NP 4 single nucleotide


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polymorphism usuall" diallelic (2%rdare %') SNPs account or *+ o ,uman genetic

variation

n t,e ,uman genome t,ere are an estimated1*$***$*** - 11$***$*** common SNPs (it,/ 1+ requenc") (d#SNP)

0ccur once in ** #ases

$***$*** SNPs ,ave #een identiied andprovisionall" mapped


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Copy Number Variants (CNVs) A Dstructura' #ariantE in the 4NA rather than a

Dse6uence #ariantE )such as a SN?-


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eions o$ enomic 4NA )1000 7ases in'enth" u( to 5 mea7ases- that can 7edu('icated or de'eted

he uman :enome ?roect shoed co(%num7er #ariation to 7e common A com(arisono$ 2 indi#idua's shoed 29 (ossi7'e CNXdi


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. Three stages of h/man )ehavior(

genetic investigation


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1. 4uantitative genetic approac,es to estimateoverall genetic variance

-5amil" (pedigree)$ tin$ & adoption designs

2. 6ene discover" approac,es (t,is ee7)

. 6ene environment interpla"$ and ot,er

unctional investigations it, identiied genes

(last unit o course)

-0verlap and integration o approac,es8 e.g.$ tindesigns used in all approac,es$ esp. 91 & 9

0. The two major cassifications of $isor$ersthat $etermine which metho$s of gene

i$entification sho/$ )e p/rs/e$


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common alleles21 rare alleles

Models of Common InheritedDisease#ommon 1isease-#ommon Cariant #ommon 1isease-


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#1#C isk a''e'es are

common" 5B

Se'ection is eak

isk mutations are o'd Limited F o$ a''e'es

o'ioenic

isk a''e'es ha#e eak

to moderate e


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. The three major metho$s of gene$iscovery3i$entification


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:. ;in7age


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areted Linkae or C%toenetic ?ositiona'candidate

?atho(h%sio'o% Candidate ene

Anima' mode's

:enomeide

3o( to look

A Linkae ana'%sisI Association Studies

0enetic linkage T to 'oci that reside(h%sica''% near each other on the samechromosome Linkae can resu't in aithin$ami'% association 7eteen a


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enetic marker and disease status

0enetic marker T (o'%mor(hic 4NA

se6uence )t%(ica''% not $unctiona'- o$knon chromosoma' 'ocation

'ecom)ination rate at hich

disease status is assoc ith di6erentenetic marker status in o LinkageQ oure=(erience ith 'inkae so$ar in this course


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Linkage nalysisformal deDnition


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Statistica' (rocedure $or ana'%!inithin$ami'% associations 7eteenenetic markers and disease

(henot%(es that takes into accountthe com('ications o$ reduced(enetrance and crossino#er

est statistic G 'od score

Lod Score (the measureof linkae)


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'od G 'o10)odds@'inkaeno

'inkae-

odds G (ro7a7i'it% 'inked at )50-

(ro7a7i'it% un'inked )G50-

)theta is the recom7ination $re6uenc% 7eteenthe marker and unknon disease ene> thetacan 7e tested at #a'ues 7eteen 0 and 50-

Lod Scores


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Lod Score !dds for Linkae

"# $%$&&&

"' $%$&&

"$ $%$&

$ $&%$

' $&&%$# $&&&%$

n early linkae study%Sherrinton et al($*++)


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areted 56115613 in (edirees)10* indi#idua's ith ** a


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S/mmary on 4in!age Anaysis

dvantages


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Keasi7'e to im('ement enomeide)s%stematic & com(rehensi#e-> don/t needto ha#e h%(otheses a7out 'ocation ormechanism

As com(ared to a'ternati#es" re'ati#e'% 'o

$a'se (ositi#e rate 1isadvantages

e6uires $ami'%stud% desin :ood $or enes o$ 'are e 'o (oer to

detect enes accountin $or 5B or 'ess o$#ariance Limited reso'ution tiht 'inkae can 7e

mi''ions o$ 7ases aa% 4oes not nd the ene" rather identies a

5. Aeic Association

Association 7eteen a''e'e status


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and (henot%(e in unre'atedindi#idua's Population-levelassociation

!tomach #ancer

- Z

I

Not I,@,@ Q%

Q%

%

%

' 4 Q%Q% 4 2>2J %%

Chaenges of Gene 6$entification


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Do$ the 1++ (utati#eassociations hich ha#e 7eenstudied three or more times"on'% + ha#e 7een consistent'%re('icatedE

irschhorn et a' )2002- DAcom(rehensi#e re#ie o$ eneticassociation studies $enetics in:edicine**5+1


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7ate New York Times8ea$ine

2(29(&:;9 7efective gene tie$ to form of manic($epressive iness


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&&(&'(&:;; Schi


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11-1*-1>>

&&('=(&:;:

Sc,i?op,renia stud" inds strong signs o ,ereditar" cause

Scientists now $o/)t they fo/n$ fa/ty gene in!e$ to menta iness

@-1>-1* Scientists see lin7age #eteen alco,olism and a single gene

-13-1

0(2(&:::

Aeport suggests t,at ,omoseBualit" is lin7ed to genes

St/$y /estions gene inf/ence on homose>/aity

1*-22-1

2(&0(&::2

6ene tie to male violence is studied

Genes $on@t $oom anyone to a ife of crime

1-*2-13

&&('&(&::9

!ariant gene tied to love o ne t,rills

May)e it@s not a gene )ehin$ a person@s thri(see!ing ways

Aeic Association

dvantagesd i i '


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as% desin to im('ement Com(ares cases #ersus contro's Hn (rinci('e" #er% hih statistica' (oer

Hn (rinci('e" can identi$% causa' aent 1isadvantages

Need to kno $unctiona' (o'%mor(hismsin a candidate ene )$or direct

association- Concern a7out $a'se(ositi#es due to

mismatchin cases and contro's)stratication 7ias T ne=t s'ide-

nic 0roup 8$ I' 4 $>%"

/yper0

/yper

! '1 $2 1&


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(1&) (1&) (1&)

Not!

#2 '1 2&

2& 1& $&&

nic 0roup 8$ I' 4 $>%"/yper

0/yper

! '1

( )

$2

( )

1&

(

"/yper

0/yper

! *

( )

$

( )

$&

(

=thnic 0roup 82 I' 4 $>


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(1&) (1&) (1&)

Not!

#2 '1 2&

2& 1& $&&

($&) ($&) ($&)

Not

!

+$ * *&

*& $& $&&

nic 0roup 8$ I' 4 $>%

"/yper

0/yper

! '1

( &)

$2

( &)

1&

( &

"/yper

0/yper

! *

( &)

$

( &)

$&

(

=thnic 0roup 82 I' 4 $>


248/311

(1&) (1&) (1&)

Not!

#2 '1 2&

2& 1& $&&

($&) ($&) ($&)

Not!

+$ * *&

*& $& $&&"

/yper0

/yper

! ##

('')

$3

(#1)

4&

('4)

Not!

$$3 ## $4&

#om)ined

I' 4 $>SF

Bhy the +ase(Positive +in$ings

!tratiDcation )ias ethnic

i t hi


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mismatching


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th et al> 2%%S#merican ournal of E$idemiolo)!, $QR2 $2J-

IriginalI'4S>R

#umulative Idds 'atio as a?unction of Pu)lication "ear


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th et al> 2%%S#merican ournal of E$idemiolo)!, $QR2 $2J-

IriginalI'4S>R

Pooled $st&2ndI'4 F>9

#umulative Idds 'atio as a?unction of Pu)lication "ear


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ith et al> 2%%S#merican ournal of E$idemiolo)!, $QR2 $2J-

IriginalI'4S>R


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5hy the .alse"6ositi-e.indins7 =thnic mismatching


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llele-speciDc Idds 'atios I's forPolymorphisms !igniDcantly

ssociated in Aeta-nalysesof lzheimer7s1isease

%ecap" +in$ing genetic effects has)een $iffic/t

= pected e6ect si es


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=xpected e6ect sizesoverestimated Winner/s curse nonre('ication

Sam('e si!es ere too sma''

Metaana'%ses 'ike'% i#e more accurateestimates

ssumption that genetic variantsare common may not al(ays )eaccurate

%et/rning to the )ig pict/re ofgene i$entification Non-targeted, genome-(ide

approaches


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approaches ?ossi7'e ith 'inkae

Vnti' recent'%" not (ossi7'e ithassociation

ar'%stae strate% eneratescandidates

Targeted approaches e>g>,

candidate gene e6uire s(ecic h%(otheses

)sometimes dri#en 7% $easi7i'it% more

%et/rning to the approaches Linkage analysis ithin $ami'%

association 7eteen marker and(henot%(e


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:enetic e


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1

1irect ssociation

Assess re'ationshi( o$ 4 'ocusto (henot%(e direct'% T

e=(ect 4 to 7e a $unctiona'(o'%mor(hism in a candidate ene

1

5ndirect ssociation

A$ A

2

AF

Assess re'ationshi( o$ 4 'ocus

indirect'% 7% determinin hethemarkers )Mi- are associated ith

disease T Midon/t need to 7e$unctiona'

8apotypes

a('ot%(e is a enera'i!ation o$ the

conce(t o$ a sin'e enot%(e to


261/311

conce(t o$ a sin'e enot%(e tomu'ti('e 'inked 'oci T re$ers to aseries o$ markers )usua''% SN?s-

8apotypes Caplot"pe is a generali?ation o t,e

concept o genot"pe to multiple loci


262/311

Aecom#ination is not random$ #ut rat,ertends to occur at D,ot spotsE

',is gives rise to #loc7s o =N:(,aplot"pes)$ ,ere t,ere is ver" little

recom#ination it,in #loc7s #ut eBtensiverecom#ination #eteen #loc7s

STOPPED HERE


263/311

8apotypes

3 :enot%(es


264/311

3 :enot%(es Tat 'ocus 1

#0at 'ocus 2

0#at 'ocus 3

a('ot%(es)a''e'es inheritedtoether on a

sement o$ thesamechromosome- #0& T0#

#

0

T

0

#

8apotype 5oc!s


265/311

don & )ecasis 2

Documents

Shackman Psyc210 Module11 NatureNurture Part2